ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.292C>T (p.Arg98Cys) (rs138945081)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2019-12-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 98 of the SGCA protein (p.Arg98Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138945081, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of SGCA-related conditions (PMID:7668821, 30107846, 9032047, 30764848). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284708). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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: 8069911, 7668821, 27120200, 22095924, 9192266, 12746421). 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.
Counsyl RCV000309945 SCV000797743 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2D 2018-02-08 no assertion criteria provided clinical testing

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