Submissions for variant NM_000543.5(SMPD1):c.96G>A (p.Trp32Ter)

dbSNP: rs786204506

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169189	SCV000220433	likely pathogenic	Niemann-Pick disease, type A	2014-06-20	criteria provided, single submitter	literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199862	SCV001370598	pathogenic	Niemann-Pick disease, type B	2020-05-01	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.96G>A (p.Trp32X) results in a premature termination codon, predicted to cause an N-terminal truncation of the encoded protein due to translation initiation at a downstream START codon or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239304 control chromosomes (gnomAD). c.96G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Niemann-Pick Disease Type B (Pittis_2004, Bonetto_2005, Fotoulaki_2007, Irun_2013, Romanello_2016). These data indicate that the variant is very likely to be associated with disease. Publications reported experimental evidence evaluating an impact on protein function, demonstrating a residual enzyme activity of ~20% in leukocytes derived from a homozygous patient (Pittis_2004), though a complete lack of enzyme activity was reported in a eukaryotic cell expression system (Dardis_2005). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219345	SCV001391280	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-07-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp32*) in the SMPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Niemann-Pick disease (PMID: 15241805, 17876723). ClinVar contains an entry for this variant (Variation ID: 188840). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001219345	SCV002806505	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-07-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169189	SCV004205536	pathogenic	Niemann-Pick disease, type A	2023-11-02	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000169189	SCV005051975	pathogenic	Niemann-Pick disease, type A	2024-02-01	criteria provided, single submitter	curation
Natera, Inc.	RCV000169189	SCV002091654	pathogenic	Niemann-Pick disease, type A	2017-12-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003947446	SCV004758120	pathogenic	SMPD1-related disorder	2024-01-13	no assertion criteria provided	clinical testing	The SMPD1 c.96G>A variant is predicted to result in premature protein termination (p.Trp32*). This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with Niemann-Pick disease type B (see for example, Table 1, Pittis et al. 2004. PubMed ID: 15241805; Fotoulaki et al. 2007. PubMed ID: 17876723; Table 1, Irun et al. 2013. PubMed ID: 23252888). This variant has not been reported in a large population database, indicating this variant is rare. In vitro experimental studies suggest this variant decreases enzymatic activity of the protein (Dardis et al. 2005. PubMed ID: 16010684). Nonsense variants in SMPD1 are expected to be pathogenic. This variant is interpreted as pathogenic.