Submissions for variant NM_000543.5(SMPD1):c.1264-1G>T

dbSNP: rs1057516454

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411029	SCV000485704	likely pathogenic	Niemann-Pick disease, type A	2016-02-01	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249050	SCV001422996	likely pathogenic	Sphingomyelin/cholesterol lipidosis	2020-01-22	criteria provided, single submitter	curation	The c.1264-1G>T variant in SMPD1 has not been previously reported in individuals with Niemann-Pick disease but has been identified in 0.001% (1/111372) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516454). 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: 370394) as likely pathogenic by Counsyl. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1, PM2 (Richards 2015).
Invitae	RCV001379856	SCV001577739	likely pathogenic	Niemann-Pick disease, type B; Niemann-Pick disease, type A	2023-09-06	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 370394). This variant has not been reported in the literature in individuals affected with SMPD1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change affects an acceptor splice site in intron 3 of the SMPD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SMPD1 are known to be pathogenic (PMID: 12369017, 15221801).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000411029	SCV002819471	likely pathogenic	Niemann-Pick disease, type A	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: SMPD1 c.1264-1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 249036 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1264-1G>T in individuals affected with Niemann-Pick Disease Type A and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000411029	SCV001163304	likely pathogenic	Niemann-Pick disease, type A		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000411029	SCV002092265	likely pathogenic	Niemann-Pick disease, type A	2017-11-30	no assertion criteria provided	clinical testing