Submissions for variant NM_000543.5(SMPD1):c.995C>A (p.Pro332His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003090728	SCV003467639	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 332 of the SMPD1 protein (p.Pro332His). This variant is present in population databases (rs202081954, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2155669). 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 SMPD1 protein function with a positive predictive value of 95%. This variant disrupts the p.Pro332 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15545621, 17011332; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003404064	SCV004105876	uncertain significance	SMPD1-related disorder	2023-02-01	criteria provided, single submitter	clinical testing	The SMPD1 c.995C>A variant is predicted to result in the amino acid substitution p.Pro332His. This variant, and other variants at the same amino acid (p.Pro332Arg and p.Pro332Leu), have been reported in both cases and controls from Parkinson disease case-control studies (Supplementary Table 3 in Zhao et al. 2021. PubMed ID: 34867278; Supplementary Table 3 in Robak et al. 2017. PubMed ID: 29140481). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6413290-C-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.