Submissions for variant NM_000543.5(SMPD1):c.785_807del (p.Leu262fs)

dbSNP: rs794727252

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175621	SCV000227145	pathogenic	not provided	2017-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984223	SCV000918248	pathogenic	Niemann-Pick disease, type B	2021-02-08	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.785_807del23 (p.Leu262ArgfsX4) 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 allele was found at a frequency of 4e-06 in 249834 control chromosomes. The variant, c.785_807del23, has not, to our knowledge, been reported in the literature in individuals affected with Niemann-Pick Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001065527	SCV001230486	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu262Argfs*4) 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 present in population databases (rs794727252, gnomAD 0.01%). 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: 195086). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248878	SCV001422554	pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The p.Leu262ArgfsTer4 variant in SMPD1 (also known as p.Leu260ArgfsTer4 due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 12712061, 15234149, 12369017, 17011332) and has been identified in 0.008% (2/24384) of African chromosomes and 0.001% (1/128550) of European (non-Finnish) chromosomes the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs794727252). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 195086) as pathogenic by EGL Genetic Diagnostics and as likely pathogenic by Integrated Genetics. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 262 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in combination with reported pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Leu262ArgfsTer4 variant is pathogenic (VariationID: 93315 198093; PMID: 12712061, 15234149, 12369017, 17011332). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the prediction that it causes loss of function, its presence in combination with other pathogenic variants in affected individuals, and its low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).
GeneDx	RCV000175621	SCV001767818	pathogenic	not provided	2020-03-09	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 23418865)
Fulgent Genetics, Fulgent Genetics	RCV001065527	SCV002809831	pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2021-10-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984222	SCV004203223	pathogenic	Niemann-Pick disease, type A	2023-08-17	criteria provided, single submitter	clinical testing
Counsyl	RCV000984222	SCV001132296	likely pathogenic	Niemann-Pick disease, type A	2014-01-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984223	SCV001132297	likely pathogenic	Niemann-Pick disease, type B	2014-01-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984222	SCV002091696	pathogenic	Niemann-Pick disease, type A	2017-08-03	no assertion criteria provided	clinical testing