Submissions for variant NM_000023.4(SGCA):c.293G>A (p.Arg98His)

gnomAD frequency: 0.00003  dbSNP: rs137852621

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000010042	SCV000220643	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2014-08-26	criteria provided, single submitter	literature only
Eurofins Ntd Llc (ga)	RCV000725507	SCV000337400	pathogenic	not provided	2018-06-12	criteria provided, single submitter	clinical testing
Invitae	RCV000010042	SCV000649766	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-01-22	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 98 of the SGCA protein (p.Arg98His). This variant is present in population databases (rs137852621, gnomAD 0.004%). This missense change has been observed in individuals with limb-girdle muscular dystrophy (PMID: 7668821, 8069911, 9192266, 12746421, 22095924, 27120200). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9435). 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 SGCA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SGCA function (PMID: 18535179, 22095924). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000010042	SCV002020099	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-06-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307361	SCV002600346	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-10-02	criteria provided, single submitter	clinical testing	Variant summary: SGCA c.293G>A (p.Arg98His) results in a non-conservative amino acid change located in the Dystroglycan-type cadherin-like domain (IPR006644) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246232 control chromosomes. c.293G>A has been reported in the literature as biallelic genotypes in multiple individuals affected with features of Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Eymard_1997, Wu_2018, Pagola-Lorz_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Gastaldello_2008). The most pronounced variant effect results in decreased expression of this alpha-Sarcoglycan mutant in beta-gamma-delta-HEK cells that could be rescued by the proteasomal inhibitor MG132 treatment. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000010042	SCV002798766	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2021-07-27	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000010042	SCV003931649	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000010042	SCV004176497	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.293G>A (p.Arg98His) variant in SGCA gene has been reported in homozygous and compound heterozygous states in multiple individuals affected with muscular dystrophy (Fayssoil et al., 2016; Ljunggren et al., 1995). Experimental studies have shown that this missense change affects SGCA function (Gastaldello et al., 2008). This variant is reported with allele frequency of 0.002% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg98His in SGCA is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 98 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. In absence of another reportable variant in SGCA gene, the molecular diagnosis is not confirmed.
Baylor Genetics	RCV000010042	SCV004203153	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-10-20	criteria provided, single submitter	clinical testing
OMIM	RCV000010042	SCV000030263	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	1994-08-26	no assertion criteria provided	literature only
Natera, Inc.	RCV000010042	SCV001453378	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2020-09-16	no assertion criteria provided	clinical testing