Submissions for variant NM_000543.5(SMPD1):c.1406A>G (p.Tyr469Cys)

dbSNP: rs267607074

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Huiwen Zhang's lab, Shanghai Jiao Tong University School of Medicine, Xinhua Hospital	RCV001281423	SCV001468728	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2020-12-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001281423	SCV002274144	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-11-19	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr469 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19405096, 30795770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 992707). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 33675270). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 469 of the SMPD1 protein (p.Tyr469Cys).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235538	SCV003934640	uncertain significance	not specified	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1406A>G (p.Tyr469Cys) results in a non-conservative amino acid change located in the metallophosphatase domain (IPR041805) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251494 control chromosomes (gnomAD). c.1406A>G has been reported in the literature as a compound heterozygous genotype in two individuals affected with Niemann-Pick Disease (Hu_2021). This report suggests the variant may be associated with Niemann-Pick Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same amino acid (p.Y469S) has been associated with Niemann-Pick disease in the HGMD database and classified as pathogenic in ClinVar, suggesting Tyr469 may be important for protein function. The following publication has been ascertained in the context of this evaluation (PMID: 33675270). Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.