ClinVar Miner

Submissions for variant NM_015160.3(PMPCA):c.667C>T (p.Arg223Cys)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
3billion, Medical Genetics RCV003314361 SCV004013642 uncertain significance Autosomal recessive spinocerebellar ataxia 2 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.35; 3Cnet: 0.84). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PMPCA related disorder (PMID: 32369273). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.
Labcorp Genetics (formerly Invitae), Labcorp RCV005102864 SCV005829903 uncertain significance not provided 2024-05-02 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 223 of the PMPCA protein (p.Arg223Cys). This variant is present in population databases (rs771359205, gnomAD 0.003%). This missense change has been observed in individual(s) with spinocerebellar ataxia (PMID: 33272776). 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: 2572476). 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 PMPCA protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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