Submissions for variant NM_001130987.2(DYSF):c.4993G>A (p.Val1665Ile)

gnomAD frequency: 0.00057  dbSNP: rs147056383

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080298	SCV000112193	likely benign	not specified	2017-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000669830	SCV000794620	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-10-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086563	SCV001005736	benign	Qualitative or quantitative defects of dysferlin	2024-01-31	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000080298	SCV001143822	likely benign	not specified	2020-11-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086563	SCV001298480	uncertain significance	Qualitative or quantitative defects of dysferlin	2017-04-27	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000864868	SCV002504360	likely benign	not provided	2020-06-15	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000080298	SCV003844905	benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4876G>A (p.Val1626Ile) results in a conservative amino acid change located in the C2 domain (IPR000008) of 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 0.00074 in 251312 control chromosomes, predominantly at a frequency of 0.0096 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-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 East Asian origin. It has also been reported at a frequency of 0.0044 in control individuals of Japanese ancestry in the Japanese Whole Genome Reference Panel (ToMMo 38KJPN), including 3 homozygotes. c.4876G>A has been reported in the literature in individuals of East Asian ancestry affected with or suspected of Limb-Girdle Muscular Dystrophy/Dysferlinopathy, without strong evidence for pathogenicity, including one case where it was found in cis with a pathogenic variant, providing supporting evidence for a benign role (e.g. Yu_2017, Liu_2018, Zhong_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. The majority classified the variant as benign (n=1)/likely benign (n=4), two classified the variant as VUS, and one as pathogenic. Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000864868	SCV004154974	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	DYSF: BS1
Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology	RCV000864868	SCV001244912	pathogenic	not provided	2019-07-01	no assertion criteria provided	reference population
Natera, Inc.	RCV000669830	SCV001459367	likely benign	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-01-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952509	SCV004774973	likely benign	DYSF-related disorder	2024-03-12	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).