Submissions for variant NM_015160.3(PMPCA):c.1099G>A (p.Val367Met)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Revvity Omics, Revvity	RCV003130276	SCV003811206	uncertain significance	Autosomal recessive spinocerebellar ataxia 2	2021-04-07	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003130276	SCV004100628	uncertain significance	Autosomal recessive spinocerebellar ataxia 2		criteria provided, single submitter	clinical testing	The missense variant p.V367M in PMPCA (NM_015160.3) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.V367M variant is observed in 1/1,13,622 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.V367M missense variant is predicted to be damaging by both SIFT and PolyPhen2.The valine residue at codon 367 of PMPCA is conserved in all mammalian species. The nucleotide c.1099 in PMPCA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
GeneDx	RCV004593214	SCV005079488	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV004593214	SCV005787868	uncertain significance	not provided	2024-06-02	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 367 of the PMPCA protein (p.Val367Met). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of PMPCA-related conditions (external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2435094). 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%. 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.