Submissions for variant NM_000543.5(SMPD1):c.1829G>A (p.Arg610His)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003785695	SCV004604126	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 610 of the SMPD1 protein (p.Arg610His). This variant is present in population databases (rs140269316, gnomAD 0.008%). This missense change has been observed in individual(s) with Parkinson’s disease (PMID: 30788890, 34867278). 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.Arg610 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34660203). 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	RCV004741711	SCV005364560	uncertain significance	SMPD1-related disorder	2024-07-31	no assertion criteria provided	clinical testing	The SMPD1 c.1829G>A variant is predicted to result in the amino acid substitution p.Arg610His. This variant was reported in an individuals with Parkinson's disease (Zhao et al 2021. PubMed ID: 34867278; Alcalay et al 2019. PubMed ID: 30788890) and in a patient with acid sphingomyelinase deficiency (ASMD) (Sechi et al 2021. PubMed ID: 34660203) . This variant is reported in 0.0081% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6415770-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.