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

gnomAD frequency: 0.00004  dbSNP: rs398123787

Total submissions: 12

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000536105	SCV000649686	pathogenic	Qualitative or quantitative defects of dysferlin	2024-10-31	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; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 94321). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	2024-02-25	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000080287	SCV005413447	pathogenic	not provided	2024-08-28	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PM1, PM2, PM3_strong, PS4
Fulgent Genetics, Fulgent Genetics	RCV005025137	SCV005659318	pathogenic	Miyoshi muscular dystrophy 1; Autosomal recessive limb-girdle muscular dystrophy type 2B; Distal myopathy with anterior tibial onset	2024-05-29	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000177998	SCV001452770	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2B	2020-09-16	no assertion criteria provided	clinical testing