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

dbSNP: rs778673716

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001862659	SCV002287826	uncertain significance	Qualitative or quantitative defects of dysferlin	2022-06-20	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). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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 Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	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
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