ClinVar

Description

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).