ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.4307G>A (p.Gly1436Asp)

gnomAD frequency: 0.00004  dbSNP: rs398123787
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genetic Medicine Research, Children's National Medical Center RCV000177998 SCV000265778 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2015-12-01 criteria provided, single submitter research
Eurofins Ntd Llc (ga) RCV000080287 SCV000331195 pathogenic not provided 2016-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000080287 SCV000589325 pathogenic not provided 2017-09-26 criteria provided, single submitter clinical testing The G1418D pathogenic variant in the DYSF gene has been previously reported, in both the homozygous and compound heterozygous state, in multiple individuals with DYSF-related disorders who had decreased or absent dysferlin expression (Rosas-Vargas et al., 2007; Kesari et al., 2008; Nagaraju et al., 2008; Ankala et al., 2014).The G1418D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret G1418D as a pathogenic variant.
Athena Diagnostics RCV000080287 SCV000613210 pathogenic not provided 2015-12-01 criteria provided, single submitter clinical testing
Invitae RCV000536105 SCV000649686 pathogenic Qualitative or quantitative defects of dysferlin 2024-01-20 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1418 of the DYSF protein (p.Gly1418Asp). This variant is present in population databases (rs398123787, gnomAD 0.03%). This missense change has been observed in individuals with limb-girdle muscular dystrophy type 2B (LGMD2B) (PMID: 18276788, 18294055, 24488599; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 94321). 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%. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000177998 SCV000795301 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2017-11-02 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000080287 SCV002021879 pathogenic not provided 2023-12-06 criteria provided, single submitter clinical testing
Baylor Genetics RCV003460751 SCV004194173 pathogenic Miyoshi muscular dystrophy 1 2023-10-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003993797 SCV004813981 pathogenic Autosomal recessive limb-girdle muscular dystrophy 2024-02-20 criteria provided, single submitter clinical testing Variant summary: DYSF c.4253G>A (p.Gly1418Asp) 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 allele was found at a frequency of 4e-05 in 251390 control chromosomes, found exclusively within the Latino subpopulation at a frequency of 0.00029 in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in DYSF causing Autosomal Recessive Limb-Girdle Muscular Dystrophy (0.00029 vs 0.0031), allowing no conclusion about variant significance. c.4253G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy (e.g. Rosas-Vargas_2007, Kesari_2008, Nagaraju_2008, Ankala_2014) . These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 24488599, 18832576, 18276788, 18294055). ClinVar contains an entry for this variant (Variation ID: 94321). Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV000177998 SCV001452770 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2B 2020-09-16 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.