The heterozygous p.Gly234Glu 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). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015).
ClinVar Genomic variation as it relates to human health
NM_000070.3(CAPN3):c.701G>A (p.Gly234Glu)
Germline
Classification
Help
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.
(6)
Help
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/Likely pathogenic
6
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.701G>A (p.Gly234Glu)
Variation ID: 501754 Accession: VCV000501754.11
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q15.1 15: 42388996 (GRCh38) [ NCBI UCSC ] 15: 42681194 (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 2, 2018 Oct 26, 2024 Oct 2, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000070.3:c.701G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000061.1:p.Gly234Glu missense NM_024344.2:c.701G>A NP_077320.1:p.Gly234Glu missense NM_173087.2:c.701G>A NP_775110.1:p.Gly234Glu missense NC_000015.10:g.42388996G>A NC_000015.9:g.42681194G>A NG_008660.1:g.45894G>A LRG_849:g.45894G>A LRG_849t1:c.701G>A LRG_849p1:p.Gly234Glu - Protein change
- G234E
- Other names
- -
- Canonical SPDI
- NC_000015.10:42388995:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 2, 2023 | RCV000593803.11 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2022 | RCV000727400.5 |
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
(May 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000708238.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Likely pathogenic
(Dec 03, 2018)
|
criteria provided, single submitter
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: SCV001164503.1
First in ClinVar: Mar 01, 2020 Last updated: Mar 01, 2020 |
Comment:
The heterozygous p.Gly234Glu 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.Gly234Glu 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). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015). (less)
|
|
|
Pathogenic
(Nov 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002236395.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these … (more)
This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 501754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu). (less)
|
|
|
Likely pathogenic
(Feb 23, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004025974.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PP3, PM2_SUP, PS3, PM3
|
|
|
Pathogenic
(Oct 02, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: no
Allele origin:
germline
|
Institute of Immunology and Genetics Kaiserslautern
Accession: SCV005382201.1
First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024 |
Comment:
ACMG Criteria: PM1, PM2, PM5, PP3, PP5, PS3; Variant found in a heterzygous state
Clinical Features:
Cardiomyopathy (present) , Bicuspid aortic valve (present) , Ventricular fibrillation (present) , Sudden cardiac death (present)
|
|
|
Likely pathogenic
(Sep 24, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal recessive limb-girdle muscular dystrophy type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000794340.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
|
Comment:
Comment:
This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 501754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu).
Comment:
PP3, PM2_SUP, PS3, PM3
Comment:
ACMG Criteria: PM1, PM2, PM5, PP3, PP5, PS3; Variant found in a heterzygous state
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:
The heterozygous p.Gly234Glu 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). This variant was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies with a yeast two-hybrid model provide some evidence that the p.Gly234Glu variant may impact protein function by impairing protein binding with substrates (PMID: 9642272). However, these types of assays may not accurately represent biological function. The p.Gly234Glu variant in CAPN3 has been reported in 5 individuals with Limb-Girdle Muscular Dystrophy. The presence of this variant in combination with 4 variants (including a frameshift variant) reported pathogenic by the literature and in 4 of these individuals with LGMD increases the likelihood that the p.Gly234Glu variant is pathogenic (PMID: 16141003, 17994539, 27500519). This variant has also been reported pathogenic in ClinVar (Variation ID: 501754). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PS3_Moderate, PM3_Strong (Richards 2015).
Comment:
This missense change has been observed in individuals with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 7720071, 15689361, 16141003, 17994539, 27500519). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CAPN3 function (PMID: 9642272). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CAPN3 protein function. ClinVar contains an entry for this variant (Variation ID: 501754). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 234 of the CAPN3 protein (p.Gly234Glu).
Comment:
PP3, PM2_SUP, PS3, PM3
Comment:
ACMG Criteria: PM1, PM2, PM5, PP3, PP5, PS3; Variant found in a heterzygous state
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Cardiopulmonary dysfunction in patients with limb-girdle muscular dystrophy 2A. | Mori-Yoshimura M | Muscle & nerve | 2017 | PMID: 27500519 |
| Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. | Guglieri M | Human mutation | 2008 | PMID: 17994539 |
| Extensive scanning of the calpain-3 gene broadens the spectrum of LGMD2A phenotypes. | Piluso G | Journal of medical genetics | 2005 | PMID: 16141003 |
| 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 |
| Functional defects of a muscle-specific calpain, p94, caused by mutations associated with limb-girdle muscular dystrophy type 2A. | Ono Y | The Journal of biological chemistry | 1998 | PMID: 9642272 |
| 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 | - | - | - | - |
Text-mined citations for rs1555420634 ...
HelpThese 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 03, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.