ClinVar Genomic variation as it relates to human health

The c.1493G>T (p.Arg498Leu) missense variant in the SMPD1 gene has been previously reported in multiple individuals affected with Niemann-Pick Disease Type A (Ricci et al., 2004; Levran et al., 1991). This variant is reported by GeneReviews (Wasserstein and Schuchman, 2015) to be one of three variants that account for over 90% of the cases of Niemann-Pick Disease Type A in individuals of Ashkenazi Jewish ancestry. SMPD1 is the only gene known to cause Niemann-Pick Disease Type A. Furthermore, molecular modeling suggests that the amino acid affected by this variant is near the active site of a metallophosphoesterase-like domain; an in vitro functional assay demonstrated that this variant resulted in reduced enzymatic activity, and mice with this variant also demonstrate very low SMPD1 enzymatic activity in the brain (Jones et al., 2008). This variant is absent or reported at low frequency in the population databases (Exome Sequencing Project = 0.12%%; 1000 Genomes = NA; and ExAC = 0.012%). It has also been shown to segregate with disease in one family over multiple generations (Levran et al., 1991). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP=4.68; CADD = 19.51; PolyPhen = 1.0; SIFT = 0.01). Emory Genetics Laboratory has classified this variant as Pathogenic. Therefore, this collective evidence supports the classification of the c.1493G>T (p.Arg498Leu) as a Pathogenic variant for Niemann-Pick Disease Type A. We have confirmed this finding in our laboratory using Sanger sequencing.

Variant summary: The SMPD1 c.1493G>T (p.Arg498Leu also known as c.1487G>T (p.Arg496Leu) variant located in the Calcineurin-like phophoesterase domain (via InterPro) causes a missense change involving the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, which is supported by a functional study, Levran_1992. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 14/121136 (1/8650), which does not exceed the estimated maximal expected allele frequency for a pathogenic SMPD1 variant of 1/447. Multiple publications cite the variant to be found in homozygous and compound heterozygous patients diagnosed with both Niemann-Pick Disease type A and B (0.0022361). In addition, multiple clinical diagnostic laboratories classify the variant as pathogenic for both types as well. Therefore, the variant of interest has been classified as "pathogenic."

NM_000543.4(SMPD1):c.1493G>T(R498L, aka R496L) is classified as pathogenic in the context of Niemann-Pick disease. Sources cited for classification include the following: PMID 21502868, 18815062 and 2023926. Classification of NM_000543.4(SMPD1):c.1493G>T(R498L, aka R496L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Common pathogenic variant in Ashkenazi Jewish patients with neuronopathic acid sphingomyelinase deficiency, also known as Niemann-Pick disease, type A (Levran et al., 1991); Functional studies found R498L is associated with less than 2% of wild-type enzyme activity (Jones et al., 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 1885770, 18815062, 21228398, 2023926, 15221801, 26169695, 30153451, 21502868, 1391960, 26320887)

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 498 of the SMPD1 protein (p.Arg498Leu). This variant is present in population databases (rs120074117, gnomAD 0.3%). This missense change has been observed in individual(s) with Niemann-Pick disease types A and B (PMID: 1391960, 1885770, 2023926). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 1391960, 1885770, 2023926). This variant is also known as R496L. ClinVar contains an entry for this variant (Variation ID: 2980). 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: 1391960, 18815062). For these reasons, this variant has been classified as Pathogenic.

The c.1493G>T (p.R498L) alteration is located in exon 6 (coding exon 6) of the SMPD1 gene. This alteration results from a G to T substitution at nucleotide position 1493, causing the arginine (R) at amino acid position 498 to be replaced by a leucine (L). Based on data from the Genome Aggregation Database (gnomAD) database, the SMPD1 c.1493G>T alteration was observed in 0.01% (36/282454) of total alleles studied, with a frequency of 0.28% (29/10346) in the Ashkenazi Jewish subpopulation. This mutation (also referred to as p.R496L) has been reported in the homozygous and compound heterozygous states in patients with SMPD1-related Niemann-Pick disease and is a common mutation in the Ashkenazi Jewish population (Levran, 1991; Ricci, 2004; Cox, 2018). Other alterations at this amino acid position have also been reported in affected patients (Simonaro, 2002; Ricci, 2004). Functional studies demonstrated reduced enzymatic activity in patient fibroblasts and transgenic mice with this mutation (Jones, 2008). The p.R498L alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

The p.Arg498Leu variant in SMPD1 (also known as p.Arg496Leu due to a difference in cDNA numbering) has been reported in at least 5 individuals with Niemann-Pick disease (PMID: 2023926, 29995201, 15221801, 18815062) and has been identified in 0.280% (29/10346) of Ashkenazi Jewish chromosomes and 0.005% (6/128826) 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 not high enough to rule out a pathogenic role due to the increased carrier frequency of this variant in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (VariationID: 2980) as pathogenic by 8 submitters. Animal models in mice have shown that this variant causes Niemann-Pick disease (PMID: 18815062). In vitro functional studies provide additional evidence that the p.Arg498Leu 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 3 affected homozygotes and in combination with a reported pathogenic variant in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg498Leu variant is pathogenic (VariationID: 198093; PMID: 2023926, 29995201, 15221801, 18815062). 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: 18815062). Multiple variants in the same region as p.Arg498Cys 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: 167712, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on mouse models, the presence of the variant in affected homozygotes and compound heterozygotes, and the phenotype of individuals with the variant being highly specific for severe disease. ACMG/AMP Criteria applied: PM3_strong, PS3, PP3, PP4, PM1 (Richards 2015).

The SMPD1 c.1493G>T variant is predicted to result in the amino acid substitution p.Arg498Leu. This variant has been reported in individuals with Niemann-Pick disease type A (referred to as R496L, Levran et al. 1991. PubMed ID: 2023926). This variant is reported to be one of three variants that account for approximately 90% of pathogenic alleles in individuals of Ashkenazi Jewish ancestry (Wasserstein and Schuchman et al. 2021. PubMed ID: 20301544). In vitro, in situ, and in vivo experimental studies indicate that this variant almost completely abolishes the enzyme activity of the SMPD1 protein (referred to as R496L, Jones et al 2008. PubMed ID: 18815062). This variant is reported in 0.28% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, but is not observed in individuals of non-Ashkenazi Jewish ancestry. Alternate nucleotide changes affecting the same amino acid (p.Arg498Cys, p.Arg498His, and p.Arg498Pro) have been reported in individuals with Niemann-Pick disease type A (Simonaro et al. 2002. PubMed ID: 12369017; Ricci et al. 2004. PubMed ID: 15221801; Hu et al. 2021. PubMed ID: 33675270). The c.1493G>T (p.Arg498Leu) variant is interpreted as pathogenic.

1 of 3 common variants that accounts for more than 90% of pathogenic variants in persons of Ashkenazi Jewish ancestry with Niemann-Pick disease type-A