Submissions for variant NM_000543.5(SMPD1):c.1474G>A (p.Gly492Ser)

gnomAD frequency: 0.00111  dbSNP: rs144873307

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514622	SCV000610587	uncertain significance	not provided	2017-06-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000514622	SCV000702522	uncertain significance	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780733	SCV000918243	uncertain significance	not specified	2024-08-06	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1474G>A (p.Gly492Ser) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 251524 control chromosomes, predominantly at a frequency of 0.0015 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type B (0.00093 vs 0.0022), allowing no conclusion about variant significance. c.1474G>A has been reported in the literature as a biallelic genotype in compound heterozygosity with a different pathogenic variant (c.739G>A, p.Gly247Ser) in two individuals, one of whom was reportedly asymptomatic and the other affected with Niemann-Pick Disease Type B (example, Irun_2013). These data do not allow unequivocal conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in-vitro, however, due to the compound heterozygous genotype, does not allow convincing conclusions about the variant effect in isolation (Irun_2013). The following publications have been ascertained in the context of this evaluation (PMID: 25933391, 23252888, 28703315, 26499107). ClinVar contains an entry for this variant (Variation ID: 445832). Based on the evidence outlined above, the variant was classified as uncertain significance.
Illumina Laboratory Services, Illumina	RCV001004370	SCV001265040	uncertain significance	Niemann-Pick disease, type A	2017-04-27	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001247838	SCV001421285	uncertain significance	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-06-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 492 of the SMPD1 protein (p.Gly492Ser). This variant is present in population databases (rs144873307, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with Niemann-Pick disease type B (PMID: 23252888). ClinVar contains an entry for this variant (Variation ID: 445832). 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 not expected to disrupt SMPD1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248880	SCV001422559	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Gly493Ser variant in SMPD1 (also known as p.Gly491Ser due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 23252888) and has been identified in 0.152% (196/129134) of European (non-Finnish) chromosomes, 0.095% (29/30616) of South Asian chromosomes, and 0.052% (13/24950) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144873307). This variant has also been reported in ClinVar (VariationID: 445832) as a VUS by Children's Mercy Hospital and Clinics, EGL Genetic Diagnostics, Integrated Genetics, and Mayo Clinic Genetic Testing Laboratories. 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 combination with a reported likely pathogenic variant and in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Gly492Ser variant is pathogenic (VariationID: 100731; PMID: 23252888). The phenotype of individuals compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being less than 10% of normal, consistent with disease (PMID: 23252888). In summary, the clinical significance of the p.Gly492Ser variant is uncertain. ACMG/AMP Criteria applied: BS1, BP4, PM3, PP4 (Richards 2015).
GeneDx	RCV000514622	SCV001784836	uncertain significance	not provided	2022-08-08	criteria provided, single submitter	clinical testing	Reported in a patient with Parkinson disease in published literature; however, additional segregation information was not provided (Alcalay et al., 2019); Reported in the heterozygous state in a patient with a suspected lysosomal storage disease in published literature; however, the patient also harbored variants in other genes (Wang et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23252888, 28703315, 30788890, 26499107, 25933391, 34426522)
Genome-Nilou Lab	RCV001004370	SCV001806557	uncertain significance	Niemann-Pick disease, type A	2021-07-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001579139	SCV001806558	uncertain significance	Niemann-Pick disease, type B	2021-07-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002527432	SCV003714312	uncertain significance	Inborn genetic diseases	2021-04-22	criteria provided, single submitter	clinical testing	(Irun, 2013) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001579139	SCV003841203	uncertain significance	Niemann-Pick disease, type B		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001004370	SCV004807026	uncertain significance	Niemann-Pick disease, type A	2024-03-26	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000514622	SCV000801068	uncertain significance	not provided	2017-07-18	no assertion criteria provided	clinical testing
Baylor Genetics	RCV001004370	SCV001163314	uncertain significance	Niemann-Pick disease, type A	2022-05-05	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001248880	SCV001452641	uncertain significance	Sphingomyelin/cholesterol lipidosis	2020-04-03	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003942677	SCV004762222	uncertain significance	SMPD1-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The SMPD1 c.1474G>A variant is predicted to result in the amino acid substitution p.Gly492Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.