Submissions for variant NM_000543.5(SMPD1):c.1154A>G (p.Asn385Ser)

dbSNP: rs120074123

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248870	SCV001422545	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Asn385Ser variant in SMPD1 (also known as p.Asn383Ser due to a difference in cDNA numbering) has been reported in at least 1 individual with Niemann-Pick disease (PMID: 26049896, 16010684, 1618760) and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 2988) as pathogenic by OMIM. In vitro functional studies provide some evidence that the p.Asn385Ser variant may impact protein function (PMID: 26499107, 1618760). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Asn385Ser variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 26499107, 15557261). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3, PM2, PM1, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002512692	SCV003439607	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-07-14	criteria provided, single submitter	clinical testing	This variant is also known as N383S. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 385 of the SMPD1 protein (p.Asn385Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 1618760, 33675270). ClinVar contains an entry for this variant (Variation ID: 2988). 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. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 1618760). This variant disrupts the p.Asn385 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (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.
OMIM	RCV000003122	SCV000023280	pathogenic	Niemann-Pick disease, type B	1992-01-01	no assertion criteria provided	literature only