Submissions for variant NM_001130987.2(DYSF):c.3175C>T (p.Arg1059Cys)

gnomAD frequency: 0.00014  dbSNP: rs144598063

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000361984	SCV000340295	uncertain significance	not provided	2017-12-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000665677	SCV000789836	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-02-22	criteria provided, single submitter	clinical testing
Invitae	RCV000693473	SCV000821344	pathogenic	Qualitative or quantitative defects of dysferlin	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1041 of the DYSF protein (p.Arg1041Cys). This variant is present in population databases (rs144598063, gnomAD 0.04%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy and/or Miyoshi myopathy (PMID: 15469449, 33610434). ClinVar contains an entry for this variant (Variation ID: 286743). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYSF protein function. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000693473	SCV000914940	uncertain significance	Qualitative or quantitative defects of dysferlin	2017-04-27	criteria provided, single submitter	clinical testing	The DYSF c.3121C>T (p.Arg1041Cys) variant has been reported in one study and is found in one patient with Miyoshi muscular dystrophy in a homozygous state (Kawabe et al. 2004). The p.Arg1041Cys variant was absent from 120 control chromosomes and is reported at a frequency of 0.00047 in the European American population of the Exome Sequencing Project. Based on the evidence, the p.Arg1041Cys variant is classified as a variant of unknown significance but suspicious for pathogenicity for dysferlinopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Revvity Omics, Revvity	RCV000361984	SCV003829584	uncertain significance	not provided	2021-06-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000665677	SCV003841217	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2023-11-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000361984	SCV004042076	uncertain significance	not provided	2023-08-01	criteria provided, single submitter	clinical testing	DYSF: PM2, PM3, PP3
PreventionGenetics, part of Exact Sciences	RCV003401254	SCV004120534	likely pathogenic	DYSF-related condition	2023-01-23	criteria provided, single submitter	clinical testing	The DYSF c.3121C>T variant is predicted to result in the amino acid substitution p.Arg1041Cys. This variant was reported in the homozygous state in an individual with Miyoshi myopathy (Kawabe et al 2004. PubMed ID: 15469449). This variant was also reported in the compound heterozygous state in 2 additional individuals with dysferlinopathy and reduced or absent dysferlin on muscle biopsy (Supp. Table 1 in Moore U et al 2021. PubMed ID: 33610434). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-71797818-C-T). This variant is interpreted as likely pathogenic.
Natera, Inc.	RCV000665677	SCV001455215	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-01-10	no assertion criteria provided	clinical testing