Submissions for variant NM_000543.5(SMPD1):c.1785_1786del (p.Ala597fs)

dbSNP: rs1057516403

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411063	SCV000485601	likely pathogenic	Niemann-Pick disease, type A	2016-01-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000412887	SCV000490821	pathogenic	not provided	2019-12-10	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 35 amino acids are lost and replaced with 6 incorrect amino acids; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15877209, 14681755, 18052040, 26499107, 32714837)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411063	SCV000697415	pathogenic	Niemann-Pick disease, type A	2022-07-18	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1785_1786delTT (p.Ala597ProfsX7) results in a premature termination codon in the last exon that is not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing the last 35 amino acids of the encoded protein. Truncations downstream of this position have been reported in affected individuals (HGMD). The variant was absent in 250890 control chromosomes (gnomAD). c.1785_1786delTT has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type A (Pavlu-Pereira_2005, Thurberg_2020, Hu_2021). These data indicate that the variant is very likely to be associated with disease. One of these publications reported experimental evidence evaluating an impact on protein function, and demonstrated almost complete absence of enzyme activity in a liver sample derived from a homozygous patient (Pavlu-Pereira_2005). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001388425	SCV001589410	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala597Profs*7) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 35 amino acid(s) of the SMPD1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with ASM deficiency (PMID: 15877209, 26913189). ClinVar contains an entry for this variant (Variation ID: 370328). This variant disrupts a region of the SMPD1 protein in which other variant(s) (p.Arg602Valfs*11) have been determined to be pathogenic (PMID: 27338287; 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.
Baylor Genetics	RCV000411063	SCV004203226	pathogenic	Niemann-Pick disease, type A	2023-07-29	criteria provided, single submitter	clinical testing