ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs776442314
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Total submissions: 5
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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
Invitae 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.

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