ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1145_1146del (p.Leu382fs)

dbSNP: rs1057516432
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411726 SCV000485662 likely pathogenic Niemann-Pick disease, type A 2016-01-22 criteria provided, single submitter clinical testing
Baylor Genetics RCV000411726 SCV001163677 pathogenic Niemann-Pick disease, type A criteria provided, single submitter clinical testing
Invitae RCV001221943 SCV001394018 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-11-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu382Glnfs*8) 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 variant has not been reported in the literature in individuals affected with SMPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 370363). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001249040 SCV001422975 likely pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Leu382GlnfsTer8 variant in SMPD1 (also known as p.Leu380GlnfsTer8 due to a difference in cDNA numbering) has not been previously reported in individuals with Niemann-Pick disease, but has been identified in 0.001% (1/113008) of European (non-Finnish) chromosomes Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1057516432). 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: 370363) as likely pathogenic by Counsyl. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 382 and leads to a premature termination codon 8 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. 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).
PreventionGenetics, part of Exact Sciences RCV003950318 SCV004760216 likely pathogenic SMPD1-related condition 2024-02-08 criteria provided, single submitter clinical testing The SMPD1 c.1145_1146delTC variant is predicted to result in a frameshift and premature protein termination (p.Leu382Glnfs*8). To our knowledge this variant has not been reported in the literature. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SMPD1 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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