Submissions for variant NM_000543.5(SMPD1):c.1148A>G (p.Asn383Ser)

gnomAD frequency: 0.00001  dbSNP: rs776442314

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS	RCV001527424	SCV001738425	likely pathogenic	Niemann-Pick disease, type A	2021-04-25	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001873722	SCV002282936	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 383 of the SMPD1 protein (p.Asn383Ser). This variant is present in population databases (rs776442314, gnomAD 0.006%). This missense change has been observed in individuals with SMPD1-related conditions (PMID: 1618760, 26049896, 34273913). ClinVar contains an entry for this variant (Variation ID: 1173972). 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). For these reasons, this variant has been classified as Pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001527424	SCV003936012	pathogenic	Niemann-Pick disease, type A	2023-06-24	criteria provided, single submitter	clinical testing	A homozygous missense variant in exon 3 of the SMPD1 gene that results in the amino acid substitution of Serine for Asparagine at codon 383 was detected. The observed variant c.1148A>G (p.Asp383Ser) has not been reported in the 1000 genomes database and has a MAF of 0.0016% in the gnomAD databases. The in silico prediction of the variant is damaging by PolyPhen-2, DANN, SIFT and MutationTaster2. In summary, the variant meets our criteria to be classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323898	SCV004028794	pathogenic	Sphingomyelin/cholesterol lipidosis	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1148A>G (p.Asn383Ser) results in a 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 1.6e-05 in 249270 control chromosomes (gnomAD). c.1148A>G has been reported in the literature in individuals affected with SMPD1-related conditions (example: Deshpande_2021, McGovern_2016, Wasserstein_2015, Takahashi_1992). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and reported reduced enzyme activity (Takahashi_1992). The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 25834946, 8693491, 26049896). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001873722	SCV004232631	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-01-25	criteria provided, single submitter	clinical testing	A Homozygous missense variation in exon 3 of the SMPD1gene that results in the amino acid substitution of Serine for Aspargine at codon 383 was detected. The observed variant c.1148A>G (p.Asn383Ser) has not been reported in the 1000 genomes and has minor allelic frequency of 0.0016% in the gnomAD databases. The in silico prediction of the variant is disease causing by PolyPhen-2 (HumDiv), MetaLR, DANN and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.