Submissions for variant NM_001130987.2(DYSF):c.1906G>A (p.Gly636Arg)

gnomAD frequency: 0.00001  dbSNP: rs201049092

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176067	SCV000227661	uncertain significance	not provided	2014-11-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000675177	SCV000800806	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-03-29	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000675177	SCV001164491	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-12-03	criteria provided, single submitter	research	The homozygous p.Gly636Arg variant in DYSF was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Gly636Arg variant in DYSF has been reported in 6 individuals with LGMD (PMID: 26404900, 17828519, 18853459, 15469449, 26088049), and has been identified in 0.004484% (1/22300) of Finnish chromosomes and 0.004484% (1/22300) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201049092). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, the clinical significance of the p.Gly636Arg variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852168	SCV002219542	pathogenic	Qualitative or quantitative defects of dysferlin	2022-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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 DYSF protein function. ClinVar contains an entry for this variant (Variation ID: 195490). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 15469449, 18853459, 26088049, 26404900). This variant is present in population databases (rs201049092, gnomAD 0.004%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 618 of the DYSF protein (p.Gly618Arg).
Revvity Omics, Revvity	RCV000176067	SCV003833251	pathogenic	not provided	2023-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235095	SCV003933720	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-05-12	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.1852G>A (p.Gly618Arg) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251442 control chromosomes (gnomAD). c.1852G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Limb-Girdle Muscular Dystrophy or Miyoshi Myopathy with confirmed absense of DYSF protein (e.g. Kawabe_2004, Krahn_2009, Nishikawa_2016, Charnay_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33927379, 15469449, 18853459, 26088049). Four ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, two as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003468857	SCV004194182	likely pathogenic	Miyoshi muscular dystrophy 1	2023-10-09	criteria provided, single submitter	clinical testing