Submissions for variant NM_001130987.2(DYSF):c.5557C>T (p.Arg1853Cys)

gnomAD frequency: 0.00001  dbSNP: rs1280185461

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000673454	SCV000798658	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2018-03-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001141004	SCV001301317	uncertain significance	Qualitative or quantitative defects of dysferlin	2017-11-19	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). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001141004	SCV003524776	pathogenic	Qualitative or quantitative defects of dysferlin	2023-11-05	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 1814 of the DYSF protein (p.Arg1814Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with DYSF-related conditions (PMID: 21522182, 26404900). ClinVar contains an entry for this variant (Variation ID: 557327). 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 with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800529	SCV005422395	uncertain significance	not specified	2024-10-11	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.5440C>T (p.Arg1814Cys) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 233300 control chromosomes. c.5440C>T has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example: Cacciottolo_2011, Magri_2015). These data indicate that the variant may 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: 21522182, 26404900). ClinVar contains an entry for this variant (Variation ID: 557327). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.