Submissions for variant NM_000543.5(SMPD1):c.1462A>G (p.Thr488Ala)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324398	SCV004028796	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2023-07-28	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1462A>G (p.Thr488Ala) 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 251474 control chromosomes (gnomAD). c.1462A>G has been reported in the literature in at least one compound heterozygous individual affected with Niemann-Pick Disease, Type B (e.g., Rodriguez-Pascau_2009). Additionally, at least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in <5% of normal enzymatic activity (e.g., Rodriquez-Pascau_2009). Protein structural modelling studies also suggest the variant would disrupt hydrogen bonding within the protein (e.g., Zhou_2016). The following publications have been ascertained in the context of this evaluation (PMID: 19405096, 27725636). No submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.