Submissions for variant NM_000543.5(SMPD1):c.1518C>G (p.Tyr506Ter)

dbSNP: rs943924098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410839	SCV000485833	likely pathogenic	Niemann-Pick disease, type A	2016-02-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114524	SCV003800816	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2023-01-06	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1518C>G (p.Tyr506X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251394 control chromosomes. To our knowledge, no occurrence of c.1518C>G in individuals affected with Niemann-Pick Disease and no experimental evidence demonstrating its impact on protein function have been reported. However c.1518C>A, which also results in a p.Tyr506X stop-gain, was reported in a homozygous individual with Niemann-Pick disease (PMID: 34273913). One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000410839	SCV004203225	likely pathogenic	Niemann-Pick disease, type A	2023-08-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766123	SCV004584799	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr506*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acid(s) of the SMPD1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 370493). This variant disrupts a region of the SMPD1 protein in which other variant(s) (p.His516Arg) have been determined to be pathogenic (PMID: 31122880, 33675270; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.