ClinVar Genomic variation as it relates to human health

The majority of missense variants in this gene are considered pathogenic [(Stenson et al., 2014; other references)]; This variant is associated with the following publications: (PMID: 29140481, 26499107, 31589614)

The p.Arg476Gln variant in SMPD1 (also known as p.Arg474Gln due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 264991070) and has been identified in 0.016% (5/30616) of South Asian chromosomes and 0.003% (3/113764) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs763566905). 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: 285606) as likely pathogenic by GeneDx. 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 combination with reported pathogenic variant and in an individual with Niemann-Pick disease increases the likelihood that the p.Arg476Gln variant is pathogenic (VariationID: 592260; VariationID: 264991070). One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg476Trp, has been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 93315; PMID: 31122880, 12712061, 23252888, 19405096, 29995201, 12369017). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM3, PM2_supporting, PP3 (Richards 2015).

NM_000543.4(SMPD1):c.1427G>A(R476Q) is a missense variant classified as a variant of uncertain significance in the context of Niemann-Pick disease, SMPD1-related. R476Q has been observed in cases with relevant disease (PMID: 26499107). Functional assessments of this variant are not available in the literature. R476Q has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_000543.4(SMPD1):c.1427G>A(R476Q) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Variant summary: SMPD1 c.1427G>A (p.Arg476Gln) results in a conservative amino acid change located in the Acid sphingomyelinase/endopolyphosphatase, metallophosphatase domain (IPR041805) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251486 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1427G>A has been reported in the literature in one compound heterozygous individual affected with Niemann-Pick Disease (Zampieri_2015). These data do not allow any conclusion about variant significance. The variant is predicted to impact protein folding/stability when modelled using the crystal structure of the SMPD1 protein (Gorelik_2016). However, without experimental validation, this does not allow convincing conclusions about the variants' effect on protein function. A different substitution at the same codon has been previously classified as pathogenic by our laboratory (c.1426C>T [p.Arg476Trp], ClinVar: 93315), suggesting this residue is important for normal function. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, and five as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.004%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.67). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000385606). Different missense changes at the same codon (p.Arg476Gly, p.Arg476Trp) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000093315, VCV000992708 / PMID: 12369017, 33675270). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change replaces arginine with glutamine at codon 476 of the SMPD1 protein (p.Arg476Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs763566905, gnomAD 0.02%). This variant has been observed in individual(s) with SMPD1-related conditions (PMID: 26499107). ClinVar contains an entry for this variant (Variation ID: 385606). 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.Arg476 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12369017, 12712061, 15234149, 23252888; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The SMPD1 c.1427G>A variant is predicted to result in the amino acid substitution p.Arg476Gln. This variant, along with a second SMPD1 variant, was reported in an individual with Niemann-Pick disease (Zampieri et al. 2016. PubMed ID: 26499107). This variant has also been reported in an individual with Parkinson's disease (Table S3, Robak et al. 2017. PubMed ID: 29140481). Additionally, different missense variants affecting this amino acid (p.Arg476Gln, p.Arg476Gly) have been reported as pathogenic (Irun et al. 2013. PubMed ID: 23252888; Hu et al. 2021. PubMed ID: 33675270). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD and in ClinVar this variant has conflicting interpretations of uncertain, likely pathogenic, and pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/385606/). Taken together, this variant is interpreted as likely pathogenic.