ClinVar

Description

Variant summary: SMPD1 c.1550A>T (p.Glu517Val) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0023 in 251358 control chromosomes, predominantly at a frequency of 0.0037 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European originc.1550A>T has been reported in the literature in compound heterozygous individuals affected with Niemann-Pick Disease Type A (e.g. Wittmann_2012, Wasserstein_2015) and in several other patients without strong evidence for causality (e.g. Simonaro_2002, Zampieri_2015, Clark_2015). These reports do not provide unequivocal conclusions about association of the variant with Niemann-Pick Disease Type A and indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 12369017, 24767253, 23430949, 26499107, 26049896, 25933391).Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; eight submitters classified the variant as uncertain significance, while two classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.