VCV000017621.80 - ClinVar

NM_000070.3(CAPN3):c.550del (p.Thr184fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(40)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000070.3(CAPN3):c.550del (p.Thr184fs)

Variation ID: 17621 Accession: VCV000017621.80

Type and length

Deletion, 1 bp

Location

Cytogenetic: 15q15.1 15: 42387803 (GRCh38) [ NCBI UCSC ] 15: 42680001 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 4, 2013	Nov 24, 2024	Oct 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000070.3:c.549delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000070.3:c.550del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000061.1:p.Thr184fs	frameshift
NM_000070.3:c.550delA MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_024344.2:c.550del	NP_077320.1:p.Thr184fs	frameshift
NM_173087.2:c.550del	NP_775110.1:p.Thr184fs	frameshift
NC_000015.10:g.42387804del
NC_000015.9:g.42680002del
NG_008660.1:g.44702del
LRG_849:g.44702del
LRG_849t1:c.550del	LRG_849p1:p.Thr184fs

... more HGVS ... less HGVS

Protein change

T184fs

Other names

NM_000070.2:c.550del;p.Thr184Argfs*36

Canonical SPDI

NC_000015.10:42387802:AA:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA220352 Genetic Testing Registry (GTR): GTR000330880 OMIM: 114240.0009 dbSNP: rs80338800 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
CAPN3		-	-	GRCh38 GRCh37	1738	1880

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive limb-girdle muscular dystrophy type 2A	Pathogenic (15)	criteria provided, multiple submitters, no conflicts	Oct 1, 2024	RCV000019188.65
not provided	Pathogenic (10)	criteria provided, multiple submitters, no conflicts	Jun 1, 2024	RCV000078099.52
Limb-girdle muscular dystrophy, recessive	Pathogenic (1)	criteria provided, single submitter	Jun 14, 2016	RCV000348995.8
EMG: myopathic abnormalities Shoulder girdle muscle weakness	Pathogenic (1)	criteria provided, single submitter	Nov 14, 2014	RCV000414969.4
Congenital muscular dystrophy	Pathogenic (1)	criteria provided, single submitter	May 11, 2015	RCV000415373.4
Cardiac arrhythmia Elbow flexion contracture Lower-limb joint contracture Muscle weakness Muscular dystrophy	Pathogenic (1)	criteria provided, single submitter	Sep 24, 2014	RCV000415344.4
Calf muscle hypertrophy Shoulder girdle muscle weakness	Pathogenic (1)	no assertion criteria provided	Mar 29, 2016	RCV000415100.4
Muscular dystrophy	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626574.4
Limb-girdle muscle weakness Muscular dystrophy Shoulder girdle muscle weakness	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626575.4
Absent Achilles reflex Muscle weakness Myopathy	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626576.4
Absent muscle fiber calpain-3 Difficulty walking EMG: neuropathic changes Elevated circulating creatine kinase concentration Migraine Paresthesia Positive Romberg sign Progressive spinal muscular atrophy	Pathogenic (1)	criteria provided, single submitter	Jan 1, 2017	RCV000626577.4
Muscular dystrophy, limb-girdle, autosomal dominant 4	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 26, 2024	RCV001197255.8
See cases	Pathogenic (1)	criteria provided, single submitter	Apr 26, 2021	RCV001420332.4
CAPN3-related disorder	Pathogenic (2)	criteria provided, single submitter	Mar 5, 2022	RCV001849271.7
Autosomal recessive limb-girdle muscular dystrophy type 2A Muscular dystrophy, limb-girdle, autosomal dominant 4	Pathogenic (1)	criteria provided, single submitter	Jul 20, 2021	RCV002496413.2
click to load more click to collapse

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 14, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	EMG: myopathic abnormalities Shoulder girdle muscle weakness Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492667.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (May 11, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital muscular dystrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492886.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Sep 24, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Cardiac arrhythmia Lower-limb joint contracture Elbow flexion contracture Muscle weakness Muscular dystrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492972.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Absent muscle fiber calpain-3 Difficulty walking EMG: neuropathic changes Elevated circulating creatine kinase concentration Migraine Paresthesia Positive Romberg sign Progressive spinal muscular atrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747278.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747275.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Limb-girdle muscle weakness Muscular dystrophy Shoulder girdle muscle weakness Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747276.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Jan 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Absent Achilles reflex Muscle weakness Myopathy Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000747277.1 First in ClinVar: May 12, 2018 Last updated: May 12, 2018
Pathogenic (Dec 03, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001164548.1 First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020	Comment: The heterozygous p.Thr184ArgfsTer36 variant in CAPN3 was identified by our study in the compound heterozygous state with a likely pathogenic variant in one individual with … (more) The heterozygous p.Thr184ArgfsTer36 variant in CAPN3 was identified by our study in the compound heterozygous state with a likely pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in 8 homozygotes with LGMD increases the likelihood that the p.Thr184ArgfsTer36 variant is pathogenic (PMID: 27142102). This variant has been identified in 0.0002381% (66/277194) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762960425) as well as 9 additional individuals by our study. Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 184 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive Limb-Girdle Muscular Dystrophy. This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 17621). In summary, the clinial significance of p.Thr184ArgfsTer36 variant is pathogenic. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015). (less)
Pathogenic (Jan 01, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy, limb-girdle, autosomal dominant 4 Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001367892.2 First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020	Comment: This variant was classified as: Pathogenic.
Pathogenic (Mar 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	CAPN3-related disorder Affected status: yes Allele origin: germline	DASA Accession: SCV002107142.2 First in ClinVar: Mar 28, 2022 Last updated: Apr 02, 2022	Publications: PubMed (14) PubMed: 15221789‚ 15725583‚ 20635405‚ 14578192‚ 7720071‚ 21984748‚ 17318636‚ 10679950‚ 14981715‚ 16100770‚ 21204801‚ 15689361‚ 9266733‚ 26404900 Comment: The c.550delA;p.(Thr184Argfs36) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a … (more) The c.550delA;p.(Thr184Argfs36) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15221789; 15725583; 20635405) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17621; PMID: 14578192; PMID: 7720071; PMID: 21984748; PMID: 17318636; PMID: 10679950; PMID: 14981715; PMID: 16100770; PMID: 21204801; PMID: 15689361; PMID: 9266733; PMID: 15725583) - PS4. The variant is present at low allele frequencies population databases (rs80338800 – gnomAD 0.001971%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr184Argfs*36) was detected in trans with a pathogenic variant (PMID: 26404900) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. (less) Number of individuals with the variant: 1 Sex: male Geographic origin: Brazil
Pathogenic (Aug 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581700.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3, PS4_MOD, PM3, PM2_SUP, PP1	Number of individuals with the variant: 8 Sex: male
Pathogenic (Apr 22, 2021)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV000255667.5 First in ClinVar: Oct 19, 2015 Last updated: Dec 31, 2022	Publications: PubMed (25) PubMed: 26484845‚ 14578192‚ 21204801‚ 21984748‚ 10679950‚ 14981715‚ 17318636‚ 16100770‚ 9266733‚ 17702496‚ 15689361‚ 15725583‚ 7720071‚ 27142102‚ 20635405‚ 16650086‚ 16141003‚ 15351423‚ 10330340‚ 30028523‚ 28914264‚ 31788660‚ 31517061‚ 31263448‚ 30919934 Comment: This variant is one of the most common variants associated with autosomal recessive limb girdle muscular dystrophy (PMID: 17702496, 27142102, 26484845), therefore the frequency of … (more) This variant is one of the most common variants associated with autosomal recessive limb girdle muscular dystrophy (PMID: 17702496, 27142102, 26484845), therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. (less)
Pathogenic (Jul 20, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Muscular dystrophy, limb-girdle, autosomal dominant 4 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002808780.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jan 27, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000814262.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (8) PubMed: 28492532‚ 10330340‚ 15689361‚ 7720071‚ 14578192‚ 20635405‚ 21204801‚ 21984748 Comment: This sequence change creates a premature translational stop signal (p.Thr184Argfs36) in the CAPN3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Thr184Argfs36) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs762960425, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 7720071, 14578192, 20635405, 21204801, 21984748). ClinVar contains an entry for this variant (Variation ID: 17621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (May 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812575.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (3) PubMed: 7720071‚ 14981715‚ 20301490 Comment: This sequence change in CAPN3 is a frameshift variant predicted to cause a premature stop codon, p.(Thr184Argfs36), in biologically relevant exon 5/24 leading to nonsense-mediated … (more) This sequence change in CAPN3 is a frameshift variant predicted to cause a premature stop codon, p.(Thr184Argfs36), in biologically relevant exon 5/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.045% (58/129,162 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is one of the most commonly reported pathogenic variants in CAPN3 and has been detected in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy (PMID: 7720071, 14981715, 20301490). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005052051.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 26, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy, limb-girdle, autosomal dominant 4 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004211526.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Limb-Girdle Muscular Dystrophy, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000390998.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Publications: PubMed (10) PubMed: 16141003‚ 10330340‚ 10679950‚ 14981715‚ 15351423‚ 17318636‚ 16650086‚ 16100770‚ 15725583‚ 27142102 Comment: The c.550delA (p.Thr184ArgfsTer36) is a frameshift variant and is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in … (more) The c.550delA (p.Thr184ArgfsTer36) is a frameshift variant and is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in the literature. Across a selection of ten studies, the p.Thr184ArgfsTer36 variant is found in over 130 patients with limb-girdle muscular dystrophy 2 including in 54 individuals in a homozygous state, 44 in a compound heterozygous state and ten in a heterozygous state (Richard et al. 1999; Pogoda et al. 2000; Canki-Klain et al. 2004; Piluso et al. 2005; Fanin et al. 2005; Milic et al. 2005; Krahn et al. 2006; Todorova et al. 2007; ChrobÃ¡kovÃ¡ et al. 2004; Inashkina et al. 2016). The p.Thr184ArgfsTer36 variant was present in a heterozygous state in nine of 1691 healthy controls and is reported at a frequency of 0.005629 in the African American population of the Exome Sequencing Project. ChrobÃ¡kovÃ¡ et al. (2004) demonstrated an absence of the CAPN3 protein on Western blots for patients who were compound heterozygous for this variant. Based on the collective evidence and the potential impact of frameshift variants, the p.Thr184ArgfsTer36 variant is classified as pathogenic for CAPN3-related disorders. (less)
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Limb-girdle muscular dystrophy, type 2A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914668.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (10) PubMed: 10330340‚ 14981715‚ 15351423‚ 27142102‚ 15725583‚ 16100770‚ 16650086‚ 16141003‚ 17318636‚ 10679950 Comment: The CAPN3 c.550delA (p.Thr184ArgfsTer36) variant is a frameshift variant that is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well … (more) The CAPN3 c.550delA (p.Thr184ArgfsTer36) variant is a frameshift variant that is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in the literature. Across a selection of ten studies, this variant is found in over 130 patients with CAPN3-related disorders, including in 54 individuals in a homozygous state, in 44 individuals in a compound heterozygous state, and ten individuals in a heterozygous state (Richard et al. 1999; Pogoda et al. 2000; Canki-Klain et al. 2004; Piluso et al. 2005; Fanin et al. 2005; Milic et al. 2005; Krahn et al. 2006; Todorova et al. 2007; ChrobÃ¡kovÃ¡ et al. 2004; Inashkina et al. 2016). The p.Thr184ArgfsTer36 variant was present in a heterozygous state in nine of 1691 healthy controls and is reported at a frequency of 0.005629 in the African American population of the Exome Sequencing Project. ChrobÃ¡kovÃ¡ et al. (2004) demonstrated an absence of the CAPN3 protein on Western blots for patients who were compound heterozygous for this variant. Based on the collective evidence and the potential impact of frameshift variants, the p.Thr184ArgfsTer36 variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (Apr 03, 2017)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000230017.5 First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3 Number of individuals with the variant: 68 Sex: mixed
Pathogenic (Dec 20, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001194108.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 04, 2020	Publications: PubMed (1) PubMed: 17318636 Comment: NM_000070.2(CAPN3):c.550delA(aka T184Rfs36) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636. Classification of NM_000070.2(CAPN3):c.550delA(aka T184Rfs36) is … (more) NM_000070.2(CAPN3):c.550delA(aka T184Rfs36) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636. Classification of NM_000070.2(CAPN3):c.550delA(aka T184Rfs36) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Unknown mechanism) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001446548.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Exercise-induced myalgia (present) , Strabismus (present) Sex: female
Pathogenic (Feb 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV001450414.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1
Pathogenic (Apr 26, 2021)	criteria provided, single submitter (Parc Tauli Hospital Assertion Criteria 2021) Method: clinical testing	See cases (Autosomal recessive inheritance) Affected status: yes Allele origin: unknown	Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli Accession: SCV001622752.1 First in ClinVar: May 20, 2021 Last updated: May 20, 2021	Comment: PVS1_very strong;PP5_strong;PM2_supporting Clinical Features: Inguinal hernia (present) , Muscular dystrophy (present) , Abnormal molar morphology (present) , Abnormal facial shape (present) , Abnormal thorax morphology (present) , Abnormality of … (more) Inguinal hernia (present) , Muscular dystrophy (present) , Abnormal molar morphology (present) , Abnormal facial shape (present) , Abnormal thorax morphology (present) , Abnormality of the hand (present) , Pes cavus (present) , Abnormality of the Achilles tendon (present) , Peripheral neuropathy (present) , Delayed speech and language development (present) , Polycystic kidney disease (present) , Myopathy (present) , Attention deficit hyperactivity disorder (present) (less) Sex: male
Pathogenic (Jun 12, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002069199.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022	Comment: DNA sequence analysis of the CAPN3 gene demonstrated a one base pair deletion in exon 4, c.550del. This pathogenic sequence change results in an amino … (more) DNA sequence analysis of the CAPN3 gene demonstrated a one base pair deletion in exon 4, c.550del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 35 amino acids downstream of the varant, p.Thr184Argfs*36. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CAPN3 protein with potentially abnormal function. This pathogenic sequence change has previously been described in multiple patients with limb girdle muscular dystrophy and is reported to be a founder mutation in European, Russian and Amish populations (PMIDs: 17318636, 14981715). (less)
Pathogenic (Oct 06, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV002764961.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Elevated circulating creatine kinase concentration (present)
Pathogenic (Mar 17, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321501.9 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: Reported to be a founder mutation in European, Russian, La Reunion Island, and Amish populations (Richard et al., 1995; Canki-Klain et al., 2004; Todorova et … (more) Reported to be a founder mutation in European, Russian, La Reunion Island, and Amish populations (Richard et al., 1995; Canki-Klain et al., 2004; Todorova et al., 2007); Published functional studies suggest loss of normal protein function through nonsense-mediated mRNA decay (Stehlikova et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21204801, 21984748, 16001438, 16100770, 19556129, 26484845, 14981715, 16141003, 20635405, 17157502, 7720071, 14578192, 17702496, 16411092, 20517216, 27142102, 17318636, 28914264, 30028523, 30919934, 31517061, 31263448, 31788660, 31862442, 32403337, 30585608, 31127727, 34426522, 34106991, 32140910, 31589614, 33726816, 32721234, 32528171) (less)
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: unknown	3billion Accession: SCV003842012.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 7720071 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 7720071 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Gait disturbance (present) , Fasciculations (present) , Tongue fasciculations (present) , Generalized hyperreflexia (present) , Muscular atrophy (present) , Palmomental reflex (present) , Inability to … (more) Gait disturbance (present) , Fasciculations (present) , Tongue fasciculations (present) , Generalized hyperreflexia (present) , Muscular atrophy (present) , Palmomental reflex (present) , Inability to walk (present) (less)
Pathogenic (May 15, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004223979.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (4) PubMed: 10679950‚ 14578192‚ 17157502‚ 7720071 Comment: PM2, PM3, PS4_moderate, PVS1 Number of individuals with the variant: 2
Pathogenic (Nov 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002018062.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Aug 01, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005196961.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Oct 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: yes Allele origin: unknown	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001934474.3 First in ClinVar: Sep 26, 2021 Last updated: Oct 13, 2024	Comment: Criteria applied: PVS1,PS4_MOD,PS3_SUP Clinical Features: Muscular dystrophy (present) , Tetraparesis (present) Sex: female
Pathogenic (Jun 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246427.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: CAPN3: PM3:Very Strong, PVS1, PM2 Number of individuals with the variant: 18
Pathogenic (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005399588.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (3) PubMed: 27259757‚ 28881388‚ 31066050 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant negative mechanism is a suggested mechanism for dominant limb-girdle muscular dystrophy 4 (MIM#618129) associated with milder phenotypes and later age of onset (ClinVar, PMID: 27259757). (I) 0108 - This gene is associated with both recessive and dominant disease. It is predominantly reported as a recessive condition, with the dominant condition reported with only a few missense variants and one in-frame deletion (PMID: 27259757, 28881388, 31066050). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (65 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and have been observed in multiple homozygous and compound heterozygous individuals with limb girdle muscular dystrophy (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Mar 29, 2016)	no assertion criteria provided Method: clinical testing	Calf muscle hypertrophy Shoulder girdle muscle weakness Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492636.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Aug 01, 2007)	no assertion criteria provided Method: literature only	MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000039476.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 06, 2016	Publications: PubMed (3) PubMed: 14981715‚ 15725583‚ 17318636 Comment on evidence: In Croatian patients with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Canki-Klain et al. (2004) identified a 1-bp deletion (550delA) in exon 4 … (more) In Croatian patients with autosomal recessive limb-girdle muscular dystrophy type 2A (LGMDR1; 253600), Canki-Klain et al. (2004) identified a 1-bp deletion (550delA) in exon 4 of the CAPN3 gene that was the most common mutation, with a prevalence of 76% of mutant CAPN3 alleles. The detection of 4 healthy 550delA heterozygous individuals yielded a frequency of 1 in 133 (0.75%) in the general Croatian population. All 4 carriers originated from an island and mountain region near the Adriatic, indicating a probable founder effect. Fanin et al. (2005) identified the 550delA mutation in several patients with LGMD from northeastern Italy. The mutation occurred in both the homozygous state and in compound heterozygosity with another CAPN3 mutation. The 550delA mutation accounted for 9 (40%) of 23 mutant CAPN3 alleles from patients specifically from the Friuli region, and haplotype analysis indicated a founder effect. Fanin et al. (2005) concluded that LGMDR1 may be the most frequent autosomal recessive neuromuscular disorder in this region of Italy. Todorova et al. (2007) identified mutations in the CAPN3 gene in 20 (42%) of 48 unrelated Bulgarian patients with muscular dystrophy. Forty percent of the patients were homozygous for the 500delA mutation, and 70% carried it on at least 1 allele. (less)
Likely pathogenic (Dec 18, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Genetic Diseases Diagnostic Center, Koc University Hospital Accession: SCV000864408.1 First in ClinVar: Jul 01, 2019 Last updated: Jul 01, 2019
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001461307.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Apr 19, 2024)	no assertion criteria provided Method: clinical testing	CAPN3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005361536.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The CAPN3 c.550delA variant is predicted to result in a frameshift and premature protein termination (p.Thr184Argfs36). This variant is one of the most common, well … (more) The CAPN3 c.550delA variant is predicted to result in a frameshift and premature protein termination (p.Thr184Argfs36). This variant is one of the most common, well documented pathogenic variants to be causative for limb girdle muscular dystrophy (Fanin et al. 2003. PubMed ID: 14578192; Richard et al. 1999. PubMed ID: 10330340). This variant is reported in 0.045% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CAPN3 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive CAPN3-related disorders. (less)
not provided (-)	no classification provided Method: literature only	Autosomal recessive limb-girdle muscular dystrophy type 2A Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000040416.3 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (13) PubMed: 17318636‚ 14981715‚ 16100770‚ 9266733‚ 10679950‚ 15725583‚ 10330340‚ 15351423‚ 16411092‚ 17702496‚ 25135358‚ 26484845‚ 16372320 Comment: Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele (accounting for up to 75% of … (more) Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele (accounting for up to 75% of abnormal alleles) among individuals from different European countries [Richard et al 1999]. Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Russia, Croatia, Turkey, Czech Republic, Bulgaria, Germany, Italy, Poland, [Dincer et al 1997, Pogoda et al 2000, Canki-Klain et al 2004, Chrobakova et al 2004, Fanin et al 2005, Milic & Canki-Klain 2005, Balci et al 2006, Hanisch et al 2007, Todorova et al 2007, Stehlikova et al 2014, Dorobek et al 2015]. This pathogenic variant may have originated in the eastern Mediterranean region [Hermanova et al 2006]. (less)
click to load more click to collapse

Comment:

The heterozygous p.Thr184ArgfsTer36 variant in CAPN3 was identified by our study in the compound heterozygous state with a likely pathogenic variant in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in 8 homozygotes with LGMD increases the likelihood that the p.Thr184ArgfsTer36 variant is pathogenic (PMID: 27142102). This variant has been identified in 0.0002381% (66/277194) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs762960425) as well as 9 additional individuals by our study. Although this variant has been seen in the general population, the frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 184 and leads to a premature termination codon 36 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CAPN3 gene is an established disease mechanism in autosomal recessive Limb-Girdle Muscular Dystrophy. This variant has also been reported pathogenic in ClinVar by multiple submitters (Variation ID: 17621). In summary, the clinial significance of p.Thr184ArgfsTer36 variant is pathogenic. ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).

Comment:

The c.550delA;p.(Thr184Argfs*36) is a null frameshift variant (NMD) in the CAPN3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 15221789; 15725583; 20635405) - PS3_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 17621; PMID: 14578192; PMID: 7720071; PMID: 21984748; PMID: 17318636; PMID: 10679950; PMID: 14981715; PMID: 16100770; PMID: 21204801; PMID: 15689361; PMID: 9266733; PMID: 15725583) - PS4. The variant is present at low allele frequencies population databases (rs80338800 – gnomAD 0.001971%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Thr184Argfs*36) was detected in trans with a pathogenic variant (PMID: 26404900) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.

Comment:

This variant is one of the most common variants associated with autosomal recessive limb girdle muscular dystrophy (PMID: 17702496, 27142102, 26484845), therefore the frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Thr184Argfs*36) in the CAPN3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CAPN3 are known to be pathogenic (PMID: 10330340, 15689361). This variant is present in population databases (rs762960425, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with autosomal recessive limb-girdle muscular dystrophy type 2A (PMID: 7720071, 14578192, 20635405, 21204801, 21984748). ClinVar contains an entry for this variant (Variation ID: 17621). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

This sequence change in CAPN3 is a frameshift variant predicted to cause a premature stop codon, p.(Thr184Argfs*36), in biologically relevant exon 5/24 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.045% (58/129,162 alleles) in the European (non-Finnish) population, which is consistent with recessive disease. This variant is one of the most commonly reported pathogenic variants in CAPN3 and has been detected in the homozygous state and compound heterozygous with a second pathogenic allele in multiple individuals with limb-girdle muscular dystrophy (PMID: 7720071, 14981715, 20301490). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PM2_Supporting.

Comment:

The c.550delA (p.Thr184ArgfsTer36) is a frameshift variant and is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in the literature. Across a selection of ten studies, the p.Thr184ArgfsTer36 variant is found in over 130 patients with limb-girdle muscular dystrophy 2 including in 54 individuals in a homozygous state, 44 in a compound heterozygous state and ten in a heterozygous state (Richard et al. 1999; Pogoda et al. 2000; Canki-Klain et al. 2004; Piluso et al. 2005; Fanin et al. 2005; Milic et al. 2005; Krahn et al. 2006; Todorova et al. 2007; ChrobÃ¡kovÃ¡ et al. 2004; Inashkina et al. 2016). The p.Thr184ArgfsTer36 variant was present in a heterozygous state in nine of 1691 healthy controls and is reported at a frequency of 0.005629 in the African American population of the Exome Sequencing Project. ChrobÃ¡kovÃ¡ et al. (2004) demonstrated an absence of the CAPN3 protein on Western blots for patients who were compound heterozygous for this variant. Based on the collective evidence and the potential impact of frameshift variants, the p.Thr184ArgfsTer36 variant is classified as pathogenic for CAPN3-related disorders.

Comment:

The CAPN3 c.550delA (p.Thr184ArgfsTer36) variant is a frameshift variant that is predicted to result in premature truncation of the protein. The p.Thr184ArgfsTer36 variant is well reported in the literature. Across a selection of ten studies, this variant is found in over 130 patients with CAPN3-related disorders, including in 54 individuals in a homozygous state, in 44 individuals in a compound heterozygous state, and ten individuals in a heterozygous state (Richard et al. 1999; Pogoda et al. 2000; Canki-Klain et al. 2004; Piluso et al. 2005; Fanin et al. 2005; Milic et al. 2005; Krahn et al. 2006; Todorova et al. 2007; ChrobÃ¡kovÃ¡ et al. 2004; Inashkina et al. 2016). The p.Thr184ArgfsTer36 variant was present in a heterozygous state in nine of 1691 healthy controls and is reported at a frequency of 0.005629 in the African American population of the Exome Sequencing Project. ChrobÃ¡kovÃ¡ et al. (2004) demonstrated an absence of the CAPN3 protein on Western blots for patients who were compound heterozygous for this variant. Based on the collective evidence and the potential impact of frameshift variants, the p.Thr184ArgfsTer36 variant is classified as pathogenic for calpainopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

NM_000070.2(CAPN3):c.550delA(aka T184Rfs*36) is classified as pathogenic in the context of calpainopathy. Sources cited for classification include the following: PMID 17318636. Classification of NM_000070.2(CAPN3):c.550delA(aka T184Rfs*36) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

Comment:

DNA sequence analysis of the CAPN3 gene demonstrated a one base pair deletion in exon 4, c.550del. This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 35 amino acids downstream of the varant, p.Thr184Argfs*36. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated CAPN3 protein with potentially abnormal function. This pathogenic sequence change has previously been described in multiple patients with limb girdle muscular dystrophy and is reported to be a founder mutation in European, Russian and Amish populations (PMIDs: 17318636, 14981715).

Comment:

Reported to be a founder mutation in European, Russian, La Reunion Island, and Amish populations (Richard et al., 1995; Canki-Klain et al., 2004; Todorova et al., 2007); Published functional studies suggest loss of normal protein function through nonsense-mediated mRNA decay (Stehlikova et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21204801, 21984748, 16001438, 16100770, 19556129, 26484845, 14981715, 16141003, 20635405, 17157502, 7720071, 14578192, 17702496, 16411092, 20517216, 27142102, 17318636, 28914264, 30028523, 30919934, 31517061, 31263448, 31788660, 31862442, 32403337, 30585608, 31127727, 34426522, 34106991, 32140910, 31589614, 33726816, 32721234, 32528171)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.023%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (PMID: 7720071 / 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with recessive limb-girdle muscular dystrophy 1 (MIM#253600). Dominant negative mechanism is a suggested mechanism for dominant limb-girdle muscular dystrophy 4 (MIM#618129) associated with milder phenotypes and later age of onset (ClinVar, PMID: 27259757). (I) 0108 - This gene is associated with both recessive and dominant disease. It is predominantly reported as a recessive condition, with the dominant condition reported with only a few missense variants and one in-frame deletion (PMID: 27259757, 28881388, 31066050). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (65 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and have been observed in multiple homozygous and compound heterozygous individuals with limb girdle muscular dystrophy (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The CAPN3 c.550delA variant is predicted to result in a frameshift and premature protein termination (p.Thr184Argfs*36). This variant is one of the most common, well documented pathogenic variants to be causative for limb girdle muscular dystrophy (Fanin et al. 2003. PubMed ID: 14578192; Richard et al. 1999. PubMed ID: 10330340). This variant is reported in 0.045% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CAPN3 are expected to be pathogenic. This variant is interpreted as pathogenic for autosomal recessive CAPN3-related disorders.

Comment:

Many pathogenic variants have been observed repeatedly in different populations; the c.550delA pathogenic variant is the most common allele (accounting for up to 75% of abnormal alleles) among individuals from different European countries [Richard et al 1999]. Pathogenic variant most likely the result of a founder effect followed by genetic isolation in populations in Russia, Croatia, Turkey, Czech Republic, Bulgaria, Germany, Italy, Poland, [Dincer et al 1997, Pogoda et al 2000, Canki-Klain et al 2004, Chrobakova et al 2004, Fanin et al 2005, Milic & Canki-Klain 2005, Balci et al 2006, Hanisch et al 2007, Todorova et al 2007, Stehlikova et al 2014, Dorobek et al 2015]. This pathogenic variant may have originated in the eastern Mediterranean region [Hermanova et al 2006].

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Calpainopathy.	Adam MP	-	2022	PMID: 20301490
Phenotypic and genetic spectrum of patients with limb-girdle muscular dystrophy type 2A from Serbia.	Peric S	Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology	2019	PMID: 31788660
Next-generation sequencing approach to hyperCKemia: A 2-year cohort study.	Rubegni A	Neurology. Genetics	2019	PMID: 31517061
Limb-Girdle Muscular Dystrophies (LGMDs): The Clinical Application of NGS Analysis, a Family Case Report.	Strafella C	Frontiers in neurology	2019	PMID: 31263448
Impact of next-generation sequencing panels in the evaluation of limb-girdle muscular dystrophies.	Özyilmaz B	Annals of human genetics	2019	PMID: 31066050
Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients.	Ten Dam L	Clinical genetics	2019	PMID: 30919934
Multiparametric quantitative MRI assessment of thigh muscles in limb-girdle muscular dystrophy 2A and 2B.	Arrigoni F	Muscle & nerve	2018	PMID: 30028523
Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases.	Bergant G	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 28914264
Autosomal dominant calpainopathy due to heterozygous CAPN3 C.643_663del21.	Martinez-Thompson JM	Muscle & nerve	2018	PMID: 28881388
A heterozygous 21-bp deletion in CAPN3 causes dominantly inherited limb girdle muscular dystrophy.	Vissing J	Brain : a journal of neurology	2016	PMID: 27259757
Robust genotyping tool for autosomal recessive type of limb-girdle muscular dystrophies.	Inashkina I	BMC musculoskeletal disorders	2016	PMID: 27142102
The Frequency of c.550delA Mutation of the CANP3 Gene in the Polish LGMD2A Population.	Dorobek M	Genetic testing and molecular biomarkers	2015	PMID: 26484845
ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases.	Magri F	BMC neurology	2015	PMID: 26404900
Autosomal recessive limb-girdle muscular dystrophies in the Czech Republic.	Stehlíková K	BMC neurology	2014	PMID: 25135358
Patients with a phenotype consistent with facioscapulohumeral muscular dystrophy display genetic and epigenetic heterogeneity.	Sacconi S	Journal of medical genetics	2012	PMID: 21984748
Eosinophilic infiltration related to CAPN3 mutations: a pathophysiological component of primary calpainopathy?	Krahn M	Clinical genetics	2011	PMID: 21204801
Transcriptional and translational effects of intronic CAPN3 gene mutations.	Nascimbeni AC	Human mutation	2010	PMID: 20635405
Frequency of calpain-3 c.550delA mutation in limb girdle muscular dystrophy type 2 and isolated hyperCKemia in German patients.	Hanisch F	Clinical neuropathology	2007	PMID: 17702496
A large deletion and novel point mutations in the calpain 3 gene (CAPN3) in Bulgarian LGMD2A patients.	Todorova A	Neurogenetics	2007	PMID: 17318636
Quantitative analysis of CAPN3 transcripts in LGMD2A patients: involvement of nonsense-mediated mRNA decay.	Stehlíková K	Neuromuscular disorders : NMD	2007	PMID: 17157502
Screening of the CAPN3 gene in patients with possible LGMD2A.	Krahn M	Clinical genetics	2006	PMID: 16650086
Calpain-3 mutations in Turkey.	Balci B	European journal of pediatrics	2006	PMID: 16411092
Analysis of histopathologic and molecular pathologic findings in Czech LGMD2A patients.	Hermanová M	Muscle & nerve	2006	PMID: 16372320
Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes.	Piluso G	Journal of medical genetics	2005	PMID: 16141003
Calpainopathy (LGMD2A) in Croatia: molecular and haplotype analysis.	Milic A	Croatian medical journal	2005	PMID: 16100770
The frequency of limb girdle muscular dystrophy 2A in northeastern Italy.	Fanin M	Neuromuscular disorders : NMD	2005	PMID: 15725583
LGMD2A: genotype-phenotype correlations based on a large mutational survey on the calpain 3 gene.	Sáenz A	Brain : a journal of neurology	2005	PMID: 15689361
Mutations in Czech LGMD2A patients revealed by analysis of calpain3 mRNA and their phenotypic outcome.	Chrobáková T	Neuromuscular disorders : NMD	2004	PMID: 15351423
Molecular diagnosis in LGMD2A: mutation analysis or protein testing?	Fanin M	Human mutation	2004	PMID: 15221789
Prevalence of the 550delA mutation in calpainopathy (LGMD 2A) in Croatia.	Canki-Klain N	American journal of medical genetics. Part A	2004	PMID: 14981715
Loss of calpain-3 autocatalytic activity in LGMD2A patients with normal protein expression.	Fanin M	The American journal of pathology	2003	PMID: 14578192
High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia.	Pogoda TV	Human mutation	2000	PMID: 10679950
Calpainopathy-a survey of mutations and polymorphisms.	Richard I	American journal of human genetics	1999	PMID: 10330340
A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey.	Dinçer P	Annals of neurology	1997	PMID: 9266733
Mutations in the proteolytic enzyme calpain 3 cause limb-girdle muscular dystrophy type 2A.	Richard I	Cell	1995	PMID: 7720071
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CAPN3	-	-	-	-
click to load more click to collapse

Text-mined citations for rs80338800 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000070.3(CAPN3):c.550del (p.Thr184fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs80338800 ...