Submissions for variant NM_001130987.2(DYSF):c.1261G>A (p.Glu421Lys)

dbSNP: rs778673716

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001862659	SCV002287826	uncertain significance	Qualitative or quantitative defects of dysferlin	2024-05-20	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 389 of the DYSF protein (p.Glu389Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dysferlinopathy (PMID: 27647186, 33613410, 34559919). ClinVar contains an entry for this variant (Variation ID: 869485). 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. This variant disrupts the p.Glu389 amino acid residue in DYSF. Other variant(s) that disrupt this residue have been observed in individuals with DYSF-related conditions (PMID: 15515206, 27363342), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV003339470	SCV004048175	likely pathogenic	Miyoshi muscular dystrophy 1		criteria provided, single submitter	clinical testing	The amino acid Glu at position 421 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. This variant is reported as pathogenic in Clinvar. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Glu421Lys in DYSF is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The p.Glu421Lys variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. For these reasons, this variant has been classified as Likely Pathogenic.
Baylor Genetics	RCV003339470	SCV004194213	pathogenic	Miyoshi muscular dystrophy 1	2023-09-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001089584	SCV005411743	uncertain significance	not provided	2024-09-05	criteria provided, single submitter	clinical testing	PM2, PM3_supporting
3billion	RCV003339470	SCV005905511	uncertain significance	Miyoshi muscular dystrophy 1	2023-08-10	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.49 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.92 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with DYSF related disorder (ClinVar ID: VCV000869485 /PMID: 27647186).A different missense change at the same codon (p.Glu421Gln) has been reported to be associated with DYSF related disorder (PMID: 15515206). However the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology	RCV001089584	SCV001244903	pathogenic	not provided	2019-07-01	no assertion criteria provided	reference population