Submissions for variant NM_000543.5(SMPD1):c.730G>A (p.Gly244Arg)

gnomAD frequency: 0.00003  dbSNP: rs120074122

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723418	SCV000700335	pathogenic	not provided	2016-12-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248871	SCV001422546	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Gly244Arg variant in SMPD1 (also known as p.Gly242Arg due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 26981555, 1618760) and has been identified in 0.005% (7/128084) of European (non-Finnish) chromosomes and 0.003% (1/135346) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074122). 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: 2987) as pathogenic by OMIM 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 combination with a likely pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Asn385Ser variant is pathogenic (VariationID: 2988; PMID: 1618760). The p.Asn385Ser is located in a mutational hot spot and a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and slightly supports pathogenicity (PMID: 27725636, 1618760). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM3, PP3, PM1_supporting (Richards 2015).
Revvity Omics, Revvity	RCV000723418	SCV002023602	likely pathogenic	not provided	2021-10-28	criteria provided, single submitter	clinical testing
Invitae	RCV001851601	SCV002287070	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 244 of the SMPD1 protein (p.Gly244Arg). This variant is present in population databases (rs120074122, gnomAD 0.006%). This missense change has been observed in individuals with Niemann-Pick disease (PMID: 1618760, 26981555). This variant is also known as G242R. ClinVar contains an entry for this variant (Variation ID: 2987). 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%. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 1618760). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002468958	SCV002766079	uncertain significance	not specified	2022-11-12	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.730G>A (p.Gly244Arg) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain (IPR004843) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 279554 control chromosomes (gnomAD). c.730G>A has been reported in the literature as a biallelic genotype in individuals affected with Niemann-Pick Disease (e.g. Takahashi_1992, Reunert_2016, Hu_2021). These data indicate that the variant may be associated with disease. Experimental evidence using transfected COS-1 cells showed that the variant had approximately 40% residual activity when compared to wild-type (Takahashi_1992). Four ClinVar submitters have assessed the variant since 2014: three classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001851601	SCV002811657	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2022-01-15	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003472960	SCV004203222	likely pathogenic	Niemann-Pick disease, type A	2023-08-31	criteria provided, single submitter	clinical testing
OMIM	RCV000003121	SCV000023279	pathogenic	Niemann-Pick disease, type B	1992-01-01	no assertion criteria provided	literature only