ClinVar Genomic variation as it relates to human health

The p.Arg230His variant in SMPD1 (also known as p.Arg228His due to a difference in cDNA numbering) has been reported in 3 individuals with Niemann-Pick disease (PMID: 20386867, 15877209, 26499107) and has been identified in 0.274% (67/24490) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141387770). This variant has also been reported in ClinVar (Variation ID: 288072) as a VUS by Counsyl 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. A pathogenic variant resulting in a different amino acid change at the same position, p.Arg230His, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19405096, 17011332, 23356216, 22818240, 23252888; VariationID: 370432). The phenotype of an individual heterozygous for this variant is highly specific for Niemann-Pick disease based on reduced enzyme activity detected in an assay, consistent with disease (PMID: 15877209). This variant was reported in an unknown phase with reported pathogenic variants and in individuals with Niemann-Pick disease (PMID: 20386867, 15877209). However, this variant was also found in cis with another pathogenic variant, suggesting that it may not cause disease (PMID: 26499107). In summary, the clinical significance of the p.Arg230His variant is uncertain. ACMG/AMP Criteria applied: BS1, PM5, PP3, BP2, PP4 (Richards 2015).

NM_000543.4(SMPD1):c.689G>A(R230H) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. R230H has been observed in cases with relevant disease (PMID:15877209, 20386867, 26499107). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. R230H has been observed in population frequency databases (gnomAD: AFR 0.27%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.689G>A(R230H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the SMPD1 protein (p.Arg230His). This variant is present in population databases (rs141387770, gnomAD 0.3%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with ASM deficiency (PMID: 15877209, 20386867). This variant is also known as p.Arg228His. ClinVar contains an entry for this variant (Variation ID: 288072). 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.Arg230 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17011332, 19405096, 22818240, 27338287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Variant summary: SMPD1 c.689G>A (p.Arg230His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 246700 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1-fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease phenotype (0.0022). c.689G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with Niemann Pick disease (example, Pavlu-Pereira_2005, Desnick_2010) and as a homozygous complex allele in one individual affected with Niemann Pick disease type A (Zampieri_2016). Co-occurrences with other pathogenic variant(s) have been reported (SMPD1 1805G>A, p.R602H), providing supporting evidence for a benign role (Zampieri_2016). At-least one missense at Arg230 (c.688C>T p.Arg230Cys) has been evaluated P/LP in ClinVar. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 20386867, 15877209, 26499107). ClinVar contains an entry for this variant (Variation ID: 288072). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

PP3, PM3, PM5