ClinVar Miner

Submissions for variant NM_000023.4(SGCA):c.541C>A (p.Arg181Ser) (rs574376340)

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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 RCV000486077 SCV000342760 uncertain significance not provided 2016-06-13 criteria provided, single submitter clinical testing
GeneDx RCV000486077 SCV000574208 likely pathogenic not provided 2017-10-02 criteria provided, single submitter clinical testing The R181S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. However, a different missense variant at the same position (R181C) has been previously reported in an individual with calf hypertrophy who harbored an additional variant on the opposite SGCA allele (Boito et al., 2003). The R181S 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 semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some 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.
Counsyl RCV000675090 SCV000800612 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2D 2017-10-27 criteria provided, single submitter clinical testing
Invitae RCV000675090 SCV000831032 uncertain significance Autosomal recessive limb-girdle muscular dystrophy type 2D 2018-05-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 181 of the SGCA protein (p.Arg181Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs574376340, ExAC 0.03%). This variant has not been reported in the literature in individuals with SGCA-related disease. ClinVar contains an entry for this variant (Variation ID: 288595). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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