ClinVar Genomic variation as it relates to human health

Reported previously in association with Niemann-Pick disease, types A/B, and expression studies in 293-T cells show that D253H is associated with less than 1% of wild-type acid sphingomyelinase enzyme activity (Desnick et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 23356216, 23770607, 20386867, 23757202, 26499107, 30609409, 27659707, 32714837)

Variant summary: SMPD1 c.757G>C (p.Asp253His) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type (IPR004843) of the encoded protein sequence. Four of four 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 249222 control chromosomes. c.757G>C has been reported in the literature as a compound heterozygous genotype in at-least two clinically well characterized individuals affected with Niemann-Pick Disease Type A (example, Desnick_2010, Thurberg_2020). One of these two individuals displayed a characteristic autopsy pathology of infantile neurovisceral acid sphingomyelinase deficiency (Thurberg_2020). 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. The most pronounced variant effect results in <10% of normal acid sphingomyelinase enzyme activity in an in-vitro experimental system (example, Desnick_2010). Six 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=3). Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Asp253His variant in SMPD1 (also known as p.Asp251His due to a difference in cDNA numbering) has been reported in 1 individual with Niemann-Pick disease (PMID: 20386867), in 1 individual with a child with Niemann-Pick disease whose other parent also had a pathogenic variant in SMPD1 (VariationID: 93320), and has been identified in 0.004% (4/113028) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123479). 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: 93320) as likely pathogenic by the Laboratory for Molecular Medicine and Integrated Genetics and as pathogenic by EGL Genetic Diagnostics and GeneDx. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Asp253Glu, has been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 15877209, 15557261, 27349982). In vitro functional studies provide some evidence that the p.Asp253His variant may impact protein function (PMID: 20386867). 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. This variant was reported in combination with a reported likely pathogenic variant in an individual with Niemann-Pick disease (PMID: 20386867). The p.Asp253His 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 slightly supports pathogenicity (PMID: 27349982, 15557261). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on in vitro functional studies, the presence of another pathogenic variant in the same codon, and the residue being important for protein function and folding. ACMG/AMP Criteria applied: PS3, PM2, PM5, PP3, PM1_supporting (Richards 2015).

The p.Asp253His (NM_000543.4 c.757G>C) variant in SMPD1 has been reported in one compound heterozygous individual with acid sphingomyelinase deficiency (Niemann -Pick disease) (Desnick 2010) and one individual who had a child with Niemann-Pi ck disease type A, whose partner carried a pathogenic variant in the gene (ClinV ar https://www.ncbi.nlm.nih.gov/clinvar/variation/93320/ and personal communicat ion with Emory Genetics Laboratory). This variant has been identified in 1/65,79 4 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs398123479). Computational prediction tools and cons ervation analysis suggest that the p.Asp253His variant may impact the protein, t hough this information is not predictive enough to determine pathogenicity. In v itro functional studies provide some evidence that the p.Asp253His variant may i mpact protein function (Desnick 2010). However, these types of assays may not ac curately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, the p.Asp253His vari ant is likely pathogenic for autosomal recessive acid sphingomyelinase deficienc y, based upon observation in patients and supportive population, functional and predictive data.

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 253 of the SMPD1 protein (p.Asp253His). This variant is present in population databases (rs398123479, gnomAD 0.004%). This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 32714837). ClinVar contains an entry for this variant (Variation ID: 93320). 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: 20386867). This variant disrupts the p.Asp253 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 23356216), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

The SMPD1 c.757G>C variant is predicted to result in the amino acid substitution p.Asp253His. This variant was reported in the heterozygous state along with a second potentially causative variant in two individuals with Niemann-Pick disease, and exhibited <1% of wild-type enzymatic activity in an in vitro functional assay (Desnick et al. 2010. PubMed ID: 20386867; Thurberg. 2020. PubMed ID: 32714837). An alternate nucleotide change affecting the same amino acid (p.Asp253Glu), has been reported in individuals with SMPD1-associated disease (Pavlu-Pereira et al. 2005. PubMed ID: 15877209; Hu et al. 2021. PubMed ID: 33675270). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.