ClinVar Genomic variation as it relates to human health

ClinVar contains an entry for this variant (Variation ID: 167712). This variant is also known as c.1487G>A, p.R496H. This missense change has been observed in individuals with Niemann-Pick disease (PMID: 15221801, 27338287, 31965297, 32292456; Invitae). This variant is present in population databases (rs120074117, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 498 of the SMPD1 protein (p.Arg498His). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg498 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1391960, 1885770, 2023926). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.

The p.Arg498His variant in SMPD1 (also known as p.Arg496His due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 27338287, 15221801) and has been identified in 0.007% (2/30614) of South Asian chromosomes and 0.001% (1/113412) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074117). 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: 198095) as likely pathogenic by 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 an affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Arg498His variant is pathogenic (VariationID: 167710; PMID: 27338287, 15221801). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 27338287). Multiple variants in the same region as p.Arg498His have been reported in association with disease in ClinVar and the literature and the variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (VariationID: 2980, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg498Leu and p.Arg498Cys have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 2980, 198095; PMID: 29995201, 18815062, 15221801, 27338287, 25834946, 23356216). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM1, PM3, PP3, PP4 (Richards 2015).

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R496H); This variant is associated with the following publications: (PMID: 31589614, 15221801, 31980526, 34273913, 33083013, 27338287, 32292456, 31965297, 33675270, 35534800, 34554397, 2023926)