ClinVar Genomic variation as it relates to human health

Variant summary: SMPD1 c.748A>C (p.Ser250Arg) results in a non-conservative amino acid change located in ApaH type Calcineurin-like phosphoesterase domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-06 in 244428 control chromosomes in gnomAD. This frequency is not significantly higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease (1.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.748A>C has been reported in the literature in individuals affected with Niemann-Pick Disease Type A and B (Hollak_2012, Zhang_2013, Toth_2011, Diggelen_2005). These data indicate that the variant may 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 activity (Hollak_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The p.Ser250Arg variant in SMPD1 (also known as p.Ser248Arg due to a difference in cDNA numbering) has been reported in at least 6 individuals with Niemann-Pick disease (PMID: 16642440, 15877209, 22818240, 14681755, 23430884, 23356216) and has been identified in 0.003% (1/30578) of South Asian chromosomes and 0.001% (1/112970) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750779804). 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: 371576) as likely pathogenic by Counsyl and as pathogenic by Integrated Genetics. In vitro functional studies provide some evidence that the p.Ser250Arg variant may impact protein function (PMID: 16642440). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The presence of this variant in 1 affected homozygote and in combination with reported pathogenic and likely pathogenic variants in individuals with Niemann-Pick disease increases the likelihood that the p.Ser250Arg variant is pathogenic (VariationID: 551367, 2994; PMID: 16642440, 15877209, 22818240, 14681755, 23430884). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyselinase activity being <10% of normal, consistent with disease (PMID: 15877209, 22818240, 23356216). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM3_strong, PM2, PS3_moderate, PP4 (Richards 2015).

For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect SMPD1 protein function (PMID: 16642440). This variant has been observed in individual(s) with Niemann-Pick disease (PMID: 12556236, 15877209, 16642440, 23430884). This variant is also known as g.1208A>C, c.742A>C (S248R) in the literature. ClinVar contains an entry for this variant (Variation ID: 371576). This variant is present in population databases (rs750779804, ExAC 0.006%). This sequence change replaces serine with arginine at codon 250 of the SMPD1 protein (p.Ser250Arg). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and arginine.