Submissions for variant NM_000023.4(SGCA):c.292C>T (p.Arg98Cys)

gnomAD frequency: 0.00014  dbSNP: rs138945081

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000485521	SCV000337437	pathogenic	not provided	2018-06-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000485521	SCV000568792	likely pathogenic	not provided	2017-10-02	criteria provided, single submitter	clinical testing	The R98C variant has been reported in multiple individuals with LMGD2D who harbor an additional SGCA variant (Ljunggren et al., 1995; Duggan et al., 1997; Guglieri et al., 2008). This 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). The R98C 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 conserved in mammals within the cadherin-like domain of the SGCA protein (Sandona et al., 2009). Missense variants at the same residue (R98S/H) and in nearby residues (A93V; D97G; I103F/T) have been reported in the Human Gene Mutation Database in association with limb girdle muscular dystrophy (Stenson et al., 2014), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae	RCV000309945	SCV001217067	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 98 of the SGCA protein (p.Arg98Cys). This variant is present in population databases (rs138945081, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SGCA-related conditions (PMID: 7668821, 9032047, 30107846, 30764848). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284708). 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%. This variant disrupts the p.Arg98 amino acid residue in SGCA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7668821, 8069911, 9192266, 12746421, 22095924, 27120200). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000309945	SCV003808115	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2022-12-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000309945	SCV003931648	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-02-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000309945	SCV004203149	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2023-10-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000309945	SCV000797743	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2D	2018-02-08	no assertion criteria provided	clinical testing