Submissions for variant NM_000543.5(SMPD1):c.1430C>T (p.Pro477Leu)

gnomAD frequency: 0.00002  dbSNP: rs753508874

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169478	SCV000220924	likely pathogenic	Niemann-Pick disease, type A	2014-11-26	criteria provided, single submitter	literature only
GeneDx	RCV000521803	SCV000617730	likely pathogenic	not provided	2020-03-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17011332, 22818240, 12369017, 12556236, 15221801, 12712061, 30202406, 30548430)
Invitae	RCV000802459	SCV000942291	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 477 of the SMPD1 protein (p.Pro477Leu). This variant is present in population databases (rs753508874, gnomAD 0.009%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12556236, 12712061, 15221801, 17011332, 22818240). This variant is also known as P475L. ClinVar contains an entry for this variant (Variation ID: 189075). 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.Pro477 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 27338287), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169478	SCV001163313	pathogenic	Niemann-Pick disease, type A		criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249039	SCV001422974	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Pro477Leu variant in SMPD1 (also known as p.Pro475Leu due to a difference in cDNA numbering) has been reported in at least 9 individuals with Niemann-Pick disease, segregated with disease in 4 affected relatives from 2 families (PMID: 15221801, 12712061, 15234149, 17011332, 22818240), and has been identified in 0.008% (3/35438) of Latino chromosomes, 0.003% (1/30614) of South Asian chromosomes, and 0.002% (2/129190) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753508874). 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: 189075) as likely pathogenic by Counsyl and GeneDx. 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 phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 22818240). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on its presence in combination with reported pathogenic variants, its presence in individuals with a phenotype highly specific for Niemann-Pick disease, and co-segregation with disease. ACMG/AMP Criteria applied: PM3_very-strong, PM2, PP3, PP4, PP1 (Richards 2015).
Revvity Omics, Revvity	RCV000521803	SCV002023605	likely pathogenic	not provided	2021-08-10	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169478	SCV004027719	pathogenic	Niemann-Pick disease, type A	2023-06-21	criteria provided, single submitter	clinical testing	Criteria applied: PM3_VSTR,PM2_SUP,PP3,PP4
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000169478	SCV001133187	likely pathogenic	Niemann-Pick disease, type A	2019-09-26	no assertion criteria provided	clinical testing