Submissions for variant NM_000543.5(SMPD1):c.1519_1520del (p.Ser507fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003110064	SCV003761963	likely pathogenic	not provided	2023-01-25	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 125 amino acids are replaced with 9 different amino acids, and other loss-of-function variants have been reported downstream in HGMD.; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV005215969	SCV005857872	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-02-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser507Argfs*10) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 125 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: 2413049). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.