ClinVar Genomic variation as it relates to human health

Variant summary: SMPD1 c.1267C>T (p.His423Tyr) results in a conservative amino acid change located in the Acid sphingomyelinase/endophosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249054 control chromosomes. c.1267C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease (example, Fotoulaki_2007, Simonaro_2002) and has been cited by as one of the most common type B NPD allele among the Saudi population. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity in both in-vitro and in-situ enzyme assays (Jones_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

A Heterozygous missense variation in exon 4 of the SMPD1 gene that results in the amino acid substitution of Tyrosine for Histidine at codon 423 was detected. The observed variant c.1267C>T (p.His423Tyr) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by DANN, FATHMM, PROVEAN. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

Enzyme deficiency

Enzyme deficiency

Published functional studies demonstrate a damaging effect (Jones et al., 2008); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 33101984, 32292456, 26981555, 26499107, 27338287, 28600779, 17876723, 20301544, 12369017, 18815062)

The p.His423Tyr variant in SMPD1 (also known as p.His421Tyr due to a difference in cDNA numbering) has been reported in at least 13 individuals with Niemann-Pick disease (PMID: 12369017, 27338287, 26981555, 17876723) and has been identified in 0.002% (1/66538) of European (non-Finnish) chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs120074126). 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: 2992) as likely pathogenic by Invitae and as pathogenic by Counsyl, EGL Genetic Diagnostics, OMIM and GeneReviews. In vitro functional studies provide some evidence that the p.His423Tyr variant may impact protein function (PMID: 18815062). However, these types of assays may not accurately represent biological function. 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 at least 12 affected homozygotes and with another pathogenic variant in an affected individual increases the likelihood that the p.His423 variant is pathogenic (VariationID: 188840; PMID: 12369017, 27338287, 26981555, 17876723). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 27338287, 17876723). The p.His423Tyr variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 12369017, 18815062). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on functional studies, its location in an active site and zinc binding site, its presence in affected homozygotes, and its presence in patients with a phenotype highly specific for disease. ACMG/AMP Criteria applied: PS3, PM2, PM1, PM3, PP3, PP4 (Richards 2015).

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 423 of the SMPD1 protein (p.His423Tyr). This variant is present in population databases (rs120074126, gnomAD 0.0009%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 12369017, 17876723, 27338287, 28600779). This variant is also known as p.His421Tyr. ClinVar contains an entry for this variant (Variation ID: 2992). 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%. This variant disrupts the p.His423 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 16434659), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Found most commonly in persons from Saudi Arabia. Leads to early-onset severe form of Niemann-Pick disease type-A