Submissions for variant NM_001130987.2(DYSF):c.4631A>G (p.Tyr1544Cys)

gnomAD frequency: 0.00001  dbSNP: rs757820496

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000696171	SCV000824720	likely pathogenic	Qualitative or quantitative defects of dysferlin	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1505 of the DYSF protein (p.Tyr1505Cys). This variant is present in population databases (rs757820496, gnomAD 0.0009%). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 15469449, 21522182). ClinVar contains an entry for this variant (Variation ID: 550017). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV001784229	SCV002024432	likely pathogenic	not provided	2020-06-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001810464	SCV002060284	uncertain significance	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2021-11-17	criteria provided, single submitter	clinical testing	NM_003494.3(DYSF):c.4514A>G(Y1505C) is a missense variant classified as a variant of uncertain significance in the context of dysferlinopathy. Y1505C has been observed in cases with relevant disease (PMID: 15469449, 21522182). Functional assessments of this variant are not available in the literature. Y1505C has been observed in population frequency databases (gnomAD: NFE <0.01%). In summary, there is insufficient evidence to classify NM_003494.3(DYSF):c.4514A>G(Y1505C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235334	SCV003933719	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-05-09	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.4514A>G (p.Tyr1505Cys) 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 4e-06 in 251474 control chromosomes. c.4514A>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy in at least 3 compound heterozygous patients with marked reduction in Dysferlin in skeletal muscle (<5%), including a sibling pair (Kawabe_2004, Cacciottolo_2011). 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: 21522182, 15469449). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two submitters classified the variant as likely pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003459566	SCV004196531	likely pathogenic	Miyoshi muscular dystrophy 1	2023-05-13	criteria provided, single submitter	clinical testing