Submissions for variant NM_001130987.2(DYSF):c.2462G>A (p.Arg821His)

gnomAD frequency: 0.00001  dbSNP: rs759675023

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000269566	SCV000342609	uncertain significance	not provided	2016-06-06	criteria provided, single submitter	clinical testing
Counsyl	RCV000666599	SCV000790915	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2017-04-14	criteria provided, single submitter	clinical testing
Invitae	RCV000706501	SCV000835555	uncertain significance	Qualitative or quantitative defects of dysferlin	2022-06-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 803 of the DYSF protein (p.Arg803His). This variant is present in population databases (rs759675023, gnomAD 0.01%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 21816046, 30564623). ClinVar contains an entry for this variant (Variation ID: 288493). 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. 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.
GeneDx	RCV000269566	SCV001986177	uncertain significance	not provided	2021-04-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified as a single heterozygous variant in a patient with proximal lower extremity weakness and elevated creatine kinase levels (Rosales et al., 2011); This variant is associated with the following publications: (PMID: 21816046, 25312915)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804996	SCV002051384	uncertain significance	not specified	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: DYSF c.2408G>A (p.Arg803His) results in a non-conservative amino acid change located in the Ferlin B-domain (IPR012561) of 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 4.8e-05 in 251472 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in DYSF causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4.8e-05 vs 0.0031), allowing no conclusion about variant significance. c.2408G>A has been reported in the literature in the heterozygous state in at least one individual affected with suspected Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Rosales_2011, Nallamilli_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. 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: 25312915, 30564623, 21816046). ClinVar contains an entry for this variant (Variation ID: 288493). Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV000269566	SCV003830890	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000666599	SCV002079852	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-02-25	no assertion criteria provided	clinical testing