VCV000006667.52 - ClinVar

NM_001130987.2(DYSF):c.3946A>G (p.Ile1316Val)

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.

(18)

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.

Conflicting classifications of pathogenicity
Uncertain significance(4); Benign(4); Likely benign(4)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001130987.2(DYSF):c.3946A>G (p.Ile1316Val)

Variation ID: 6667 Accession: VCV000006667.52

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.2 2: 71602794 (GRCh38) [ NCBI UCSC ] 2: 71829924 (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	Oct 2, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001130987.2:c.3946A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001124459.1:p.Ile1316Val	missense
NM_003494.4:c.3892A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003485.1:p.Ile1298Val	missense
NM_001130455.2:c.3895A>G	NP_001123927.1:p.Ile1299Val	missense
NM_001130976.2:c.3850A>G	NP_001124448.1:p.Ile1284Val	missense
NM_001130977.2:c.3850A>G	NP_001124449.1:p.Ile1284Val	missense
NM_001130978.2:c.3892A>G	NP_001124450.1:p.Ile1298Val	missense
NM_001130979.2:c.3985A>G	NP_001124451.1:p.Ile1329Val	missense
NM_001130980.2:c.3943A>G	NP_001124452.1:p.Ile1315Val	missense
NM_001130981.2:c.3943A>G	NP_001124453.1:p.Ile1315Val	missense
NM_001130982.2:c.3988A>G	NP_001124454.1:p.Ile1330Val	missense
NM_001130983.2:c.3895A>G	NP_001124455.1:p.Ile1299Val	missense
NM_001130984.2:c.3853A>G	NP_001124456.1:p.Ile1285Val	missense
NM_001130985.2:c.3946A>G	NP_001124457.1:p.Ile1316Val	missense
NM_001130986.2:c.3853A>G	NP_001124458.1:p.Ile1285Val	missense
NC_000002.12:g.71602794A>G
NC_000002.11:g.71829924A>G
NG_008694.1:g.154172A>G
LRG_845:g.154172A>G
LRG_845t1:c.3892A>G	LRG_845p1:p.Ile1298Val
LRG_845t2:c.3946A>G	LRG_845p2:p.Ile1316Val
	O75923:p.Ile1298Val

... more HGVS ... less HGVS

Protein change

I1298V, I1316V, I1285V, I1299V, I1315V, I1284V, I1329V, I1330V

Other names

Canonical SPDI

NC_000002.12:71602793:A:G

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.

0.00180 (G)

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

1000 Genomes Project 30x 0.00156

1000 Genomes Project 0.00180

Trans-Omics for Precision Medicine (TOPMed) 0.00420

The Genome Aggregation Database (gnomAD), exomes 0.00458

Exome Aggregation Consortium (ExAC) 0.00474

The Genome Aggregation Database (gnomAD) 0.00491

Links

ClinGen: CA179991 UniProtKB: O75923#VAR_012309 OMIM: 603009.0003 dbSNP: rs121908954 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.
DYSF		-	-	GRCh38 GRCh37	4065	4114
LOC122787137	-	-	-	GRCh38	-	32

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.
Miyoshi muscular dystrophy 1	Uncertain significance (2)	criteria provided, single submitter	Jul 14, 2021	RCV000007049.17
not specified	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Feb 18, 2022	RCV000153183.28
Qualitative or quantitative defects of dysferlin	Benign (2)	criteria provided, single submitter	Jan 31, 2024	RCV000509353.20
not provided	Benign/Likely benign (5)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000658868.34
Autosomal recessive limb-girdle muscular dystrophy type 2B	Conflicting interpretations of pathogenicity (4)	criteria provided, conflicting classifications	Jul 14, 2021	RCV000681611.16
Distal myopathy with anterior tibial onset	Uncertain significance (1)	criteria provided, single submitter	Jul 14, 2021	RCV001563901.10
DYSF-related disorder	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV004547461.1

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.
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000309678.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jul 09, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332041.3 First in ClinVar: Dec 06, 2016 Last updated: May 03, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF Number of individuals with the variant: 1 Sex: mixed
Likely benign (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2B Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001135888.1 First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive limb-girdle muscular dystrophy type 2B Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001786957.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Sex: mixed
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Distal myopathy with anterior tibial onset Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001786958.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Sex: mixed
Uncertain significance (Jul 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Miyoshi muscular dystrophy 1 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001786956.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021	Sex: mixed
Benign (Sep 28, 2018)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613205.2 First in ClinVar: Dec 19, 2017 Last updated: Jan 18, 2020	Publications: PubMed (8) PubMed: 11468312‚ 16934466‚ 9731526‚ 24123366‚ 21816046‚ 20544924‚ 25807536‚ 22995991
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	DYSF-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001297889.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (6) PubMed: 9731526‚ 20544924‚ 21816046‚ 24123366‚ 22995991‚ 16934466 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Benign (Apr 10, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000512918.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 09, 2018	Comment: This variant is associated with the following publications: (PMID: 24123366, 25898921, 9731526, 25525159, 11468312, 21816046, 22995991, 16934466, 20544924, 30919934, 32528171)
Likely benign (Feb 18, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002103695.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Publications: PubMed (2) PubMed: 9731526‚ 30919934 Comment: Variant summary: DYSF c.3892A>G (p.Ile1298Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: DYSF c.3892A>G (p.Ile1298Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 248942 control chromosomes, predominantly at a frequency of 0.0072 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3892A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Liu_1998, ten Dam_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: seven classified as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign. (less)
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Qualitative or quantitative defects of dysferlin Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000649673.8 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024
Likely benign (Jul 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: SCV000780667.29 First in ClinVar: Jul 09, 2018 Last updated: Oct 20, 2024	Comment: DYSF: BP4, BS2 Number of individuals with the variant: 7
Pathogenic (Sep 01, 1998)	no assertion criteria provided Method: literature only	MIYOSHI MUSCULAR DYSTROPHY 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027245.6 First in ClinVar: Apr 04, 2013 Last updated: Jul 19, 2020	Publications: PubMed (1) PubMed: 9731526 Comment on evidence: In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy … (more) In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy with either distal onset or proximal onset, respectively, Liu et al. (1998) found compound heterozygosity for 2 missense mutations in the DYSF gene: an ATG-to-GTC transition at nucleotide 4265 (I1298V) and a CGT-to-TGT transition at nucleotide 6497 (R2042C; 603009.0004). (less)
Pathogenic (Sep 01, 1998)	no assertion criteria provided Method: literature only	MUSCULAR DYSTROPHY, LIMB-GIRDLE, AUTOSOMAL RECESSIVE 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000809051.2 First in ClinVar: Sep 29, 2018 Last updated: Jul 19, 2020	Publications: PubMed (1) PubMed: 9731526 Comment on evidence: In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy … (more) In an Italian family in which some members had Miyoshi myopathy (MMD1; 254130) and others had limb-girdle muscular dystrophy type 2B (LGMDR2; 253601), i.e., myopathy with either distal onset or proximal onset, respectively, Liu et al. (1998) found compound heterozygosity for 2 missense mutations in the DYSF gene: an ATG-to-GTC transition at nucleotide 4265 (I1298V) and a CGT-to-TGT transition at nucleotide 6497 (R2042C; 603009.0004). (less)
Benign (Jan 10, 2020)	no assertion criteria provided Method: clinical testing	Limb-girdle muscular dystrophy type 2B Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001455234.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002036696.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034040.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
not provided (-)	no classification provided Method: phenotyping only	Qualitative or quantitative defects of dysferlin Affected status: unknown Allele origin: unknown	GenomeConnect, ClinGen Accession: SCV000606886.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical … (more) GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormality of the musculature of the limbs (present) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2015-05-11 Testing laboratory interpretation: Pathogenic
click to load more click to collapse

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

Variant summary: DYSF c.3892A>G (p.Ile1298Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0046 in 248942 control chromosomes, predominantly at a frequency of 0.0072 within the Non-Finnish European subpopulation in the gnomAD database, including 6 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.0031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3892A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (examples: Liu_1998, ten Dam_2019). These reports do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: seven classified as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.

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
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
Population genomic analysis of 962 whole genome sequences of humans reveals natural selection in non-coding regions.	Yu F	PloS one	2015	PMID: 25807536
Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar.	Rodriguez-Flores JL	Human mutation	2014	PMID: 24123366
An informatics approach to analyzing the incidentalome.	Berg JS	Genetics in medicine : official journal of the American College of Medical Genetics	2013	PMID: 22995991
Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I.	Rosales XQ	Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance	2011	PMID: 21816046
Novel diagnostic features of dysferlinopathies.	Rosales XQ	Muscle & nerve	2010	PMID: 20544924
Muscle protein analysis in the detection of heterozygotes for recessive limb girdle muscular dystrophy type 2B and 2E.	Fanin M	Neuromuscular disorders : NMD	2006	PMID: 16934466
Genomic organization of the dysferlin gene and novel mutations in Miyoshi myopathy.	Aoki M	Neurology	2001	PMID: 11468312
Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.	Liu J	Nature genetics	1998	PMID: 9731526
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=DYSF	-	-	-	-

Text-mined citations for rs121908954 ...

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_001130987.2(DYSF):c.3946A>G (p.Ile1316Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908954 ...