Submissions for variant NM_000543.5(SMPD1):c.592G>C (p.Ala198Pro)

dbSNP: rs797044798

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001004576	SCV001163662	pathogenic	Niemann-Pick disease, type A	2023-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194004	SCV001363222	pathogenic	Niemann-Pick disease, type B	2019-01-21	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.592G>C (p.Ala198Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 212412 control chromosomes (gnomAD). c.592G>C has been reported in the literature in multiple individuals affected with Niemann-Pick disease type B (McGovern_2004, Simonaro_2002). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a reputable database (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000192220	SCV001422712	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Ala198Pro variant in SMPD1 has been reported in at least 10 individuals with Niemann-Pick disease (PMID: 15234149, 12369017) and has been identified in 0.001133% (1/88272) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs797044798). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 203435) as Pathogenic by GeneReviews. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. The presence of this variant in 2 affected homozygotes and in combination with a reported pathogenic variant in at least 3 individuals with NIemann-Pick disease increases the likelihood that the p.Ala198Pro variant is pathogenic (VariationID: 167709, 100731; PMID: 15234149, 12369017). In summary, the clinical significance of the p.Ala198Pro variant is uncertain. ACMG/AMP Criteria applied: PM3_strong, PM2, BP4 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852412	SCV002254408	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 198 of the SMPD1 protein (p.Ala198Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with acid sphingomyelinase deficiency (PMID: 12369017, 15234149; internal data). 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: 203425). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SMPD1 protein function. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV003488441	SCV004238691	likely pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing
GeneReviews	RCV000192220	SCV000238487	not provided	Sphingomyelin/cholesterol lipidosis		no assertion provided	literature only	Some evidence suggests that this pathogenic variant is associated with a less severe form of Niemann-Pick disease type B
Natera, Inc.	RCV001004576	SCV002091688	pathogenic	Niemann-Pick disease, type A	2021-04-30	no assertion criteria provided	clinical testing