Submissions for variant NM_000543.5(SMPD1):c.1675_1676del (p.Val559fs)

gnomAD frequency: 0.00001  dbSNP: rs759389193

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781869	SCV000920248	pathogenic	not specified	2018-08-30	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1675_1676delGT (p.Val559IlefsX19) 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. The variant allele was found at a frequency of 1.2e-05 in 246262 control chromosomes (gnomAD). c.1675_1676delGT has been reported in the literature in individuals affected with Niemann-Pick Disease ((Dardis_2005, Hollak_2012). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (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	RCV001869160	SCV002233640	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-09-06	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects SMPD1 function (PMID: 16010684). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 633426). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease type A or B (PMID: 16010684, 22818240). This variant is present in population databases (rs759389193, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Val559Ilefs*19) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the SMPD1 protein.
MGZ Medical Genetics Center	RCV001830676	SCV002581301	likely pathogenic	Niemann-Pick disease, type A	2022-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV004794452	SCV005414736	pathogenic	not provided	2024-05-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect on the SMPD1 protein and acid sphingomyelinase activity (PMID: 16010684); Frameshift variant predicted to result in abnormal protein length as the last 73 amino acids are replaced with 18 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22818240, 16010684)
Fulgent Genetics, Fulgent Genetics	RCV001869160	SCV005684537	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2024-04-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830676	SCV002092293	pathogenic	Niemann-Pick disease, type A	2017-03-17	no assertion criteria provided	clinical testing