Submissions for variant NM_000543.5(SMPD1):c.995C>G (p.Pro332Arg)

dbSNP: rs202081954

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454404	SCV000540394	uncertain significance	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in an individual with Niemann Pick disease (Simanaro 2002). MAF 0.5% in East Asian chromosomes.
Eurofins Ntd Llc (ga)	RCV000727004	SCV000704856	uncertain significance	not provided	2018-04-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000672505	SCV001264348	uncertain significance	Niemann-Pick disease, type A	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae	RCV001242152	SCV001415220	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 332 of the SMPD1 protein (p.Pro332Arg). This variant is present in population databases (rs202081954, gnomAD 0.5%). This missense change has been observed in individual(s) with Niemann-Pick type B (PMID: 15545621, 17011332; Invitae). 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: 403463). 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%. For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249055	SCV001423001	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Pro332Arg variant in SMPD1 (also known as p.Pro330Arg due to a difference in cDNA numbering) has been reported in 2 individuals with Niemann-Pick disease (PMID: 15545621, 19050888) and has been identified in 0.526% (105/19950) of East Asian chromosomes, and at lower frequencies in other populations, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs202081954). This variant has also been reported in ClinVar (VariationID: 403463) as a VUS by the Laboratory for Molecular Medicine, Counsyl, and EGL Genetic Diagnostics. 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 presence of this variant in 2 homozygotes with Niemann-Pick disease increases the likelihood that the p.Pro332Arg variant is pathogenic (PMID: 15545621). In summary, the clinical significance of the p.Pro332Arg variant is uncertain. ACMG/AMP Criteria applied: BS1, PM3, PP3 (Richards 2015).
Genome-Nilou Lab	RCV000672505	SCV001653329	likely pathogenic	Niemann-Pick disease, type A	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000454404	SCV001983516	uncertain significance	not specified	2023-02-01	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.995C>G (p.Pro332Arg) results in a non-conservative amino acid change located in the acid sphingomyelinase/endopolyphosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00045 in 251428 control chromosomes, predominantly at a frequency of 0.0056 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease phenotype (0.0022), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.995C>G has been reported in the literature in individuals affected with Niemann-Pick Disease, including at least two homozygous individuals (e.g. Simonaro_2002, Wasserstein_2004, Elliott_2016, Hu_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV001242152	SCV002060341	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-11-03	criteria provided, single submitter	clinical testing	NM_000543.4(SMPD1):c.995C>G(P332R) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. P332R has been observed in cases with relevant disease (PMID: 17011332, 19050888). Functional assessments of this variant are not available in the literature. P332R has been observed in population frequency databases (gnomAD: EAS 0.51%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.995C>G(P332R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Revvity Omics, Revvity	RCV000727004	SCV003822020	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003152604	SCV003841202	uncertain significance	Niemann-Pick disease, type B		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672505	SCV001163671	uncertain significance	Niemann-Pick disease, type A	2022-02-04	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001249055	SCV001455814	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000727004	SCV001798863	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000727004	SCV001968960	likely benign	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000672505	SCV002030775	not provided	Niemann-Pick disease, type A		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-30-2019 by Lab or GTR ID 1006. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR ) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect.