ClinVar Miner

Submissions for variant NM_000543.5(SMPD1):c.1624C>T (p.Arg542Ter)

dbSNP: rs398123478
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000179326 SCV000231558 pathogenic not provided 2017-02-17 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000700954 SCV000829733 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A 2023-12-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg542*) in the SMPD1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 90 amino acid(s) of the SMPD1 protein. This variant is present in population databases (rs398123478, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Niemann-Pick disease (PMID: 22796693, 23188845, 27338287; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 93318). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000984308 SCV001163316 pathogenic Niemann-Pick disease, type A criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000984308 SCV001363223 pathogenic Niemann-Pick disease, type A 2019-04-29 criteria provided, single submitter clinical testing Variant summary: SMPD1 c.1624C>T (p.Arg542X) 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 6.4e-05 in 251346 control chromosomes, predominantly at a frequency of 0.00049 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in SMPD1 causing Niemann-Pick Disease Type A (0.00049 vs 0.0022). c.1624C>T has been reported in the literature in multiple individuals affected with Niemann-Pick Disease Type A (Ranganath_2016). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248882 SCV001422562 pathogenic Sphingomyelin/cholesterol lipidosis 2020-01-22 criteria provided, single submitter curation The p.Arg542Ter variant in SMPD1 (also known as p.Arg540Ter due to a difference in cDNA numbering) has been reported in at least 14 individuals with Niemann-Pick disease (PMID: 22796693, 31139477, 27338287) and has been identified in 0.049% (15/30616) of South Asian chromosomes and 0.002% (1/113642) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123478). 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 on ClinVar (VariationID: 93318) as Pathogenic by EGL Genetic Diagnostics and Invitae. This nonsense variant leads to a premature termination codon at position 542. This alteration occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein without the C-terminus region, which is critical to protein function (PMID: 21098024, 18052040). Loss of function of the SMPD1 gene is an established disease mechanism in autosomal recessive Niemann-Pick disease. The presence of this variant in at least 11 affected homozygotes and in combination with reported pathogenic variants in 3 individuals with Niemann-Pick disease increases the likelihood that the p.Arg542Ter variant is pathogenic (PMID: 22796693, 31139477, 27338287). The phenotype of individuals homozygous and compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being less than 10% of normal, consistent with disease (PMID: 27338287, 22796693). In summary, this variant meets criteria to be classified as pathogenic for Niemann-Pick disease in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences in the homozygous state and with pathogenic variants in affected individuals. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong, PP4, PM2_supporting (Richards 2015).
Centogene AG - the Rare Disease Company RCV000700954 SCV001424495 pathogenic Niemann-Pick disease, type B; Niemann-Pick disease, type A criteria provided, single submitter clinical testing
Centogene AG - the Rare Disease Company RCV000984309 SCV001426620 pathogenic Niemann-Pick disease, type B criteria provided, single submitter clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251966 SCV002523367 pathogenic See cases 2019-11-29 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PS4, PM2, PM3
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000984309 SCV002817330 pathogenic Niemann-Pick disease, type B 2021-01-08 criteria provided, single submitter clinical testing A heterozygous missense variation in exon 6 of the SMPD1 gene that results in a stop codon and premature truncation of the protein at codon 2482 was detected. The observed variant c.1624C>T (p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as likely pathogenic.
Revvity Omics, Revvity RCV000179326 SCV003821696 pathogenic not provided 2022-09-11 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000984308 SCV004100841 pathogenic Niemann-Pick disease, type A 2023-10-27 criteria provided, single submitter clinical testing A homozygous variation in exon 6 of the SMPD1 gene that results in a premature truncation of the protein at codon 542 was detected. The observed variant c.1624C>T(p.Arg542Ter) has not been reported in the 1000 genomes and has a MAF of 0.006% in gnomAD database. The in silico prediction of the variant is disease causing by DANN and MutationTaster. In summary, the variant meets our criteria to be classified as pathogenic.
GeneDx RCV000179326 SCV005201205 pathogenic not provided 2022-01-31 criteria provided, single submitter clinical testing Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 90 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 33083013, 32860008, 27338287, 31139477, 22796693, 23188845, 33675270, 35534800)
Neuberg Centre For Genomic Medicine, NCGM RCV000984308 SCV005373574 uncertain significance Niemann-Pick disease, type A 2023-06-02 criteria provided, single submitter clinical testing The observed stop gained variant c.1624C>T(p.Arg542Ter) in the SMPD1 gene has been reported previously in multiple individuals affected with Niemann-Pick disease. In this study the p. (Arg542*) (c.1624C>T) mutation was the most commonly identified mutation, found in 22% (26 out of 120) of the alleles tested, but haplotype analysis for this mutation did not identify a founder effect for the Indian population (Ranganath P, et al., 2016). Though this variant is present in the last exon, there are other pathogenic variants reported beyond this position in the ClinVar database. This variant is reported with the allele frequency 0.01% in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Likely pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000984308 SCV001132491 likely pathogenic Niemann-Pick disease, type A 2015-04-24 no assertion criteria provided clinical testing
Counsyl RCV000984309 SCV001132492 likely pathogenic Niemann-Pick disease, type B 2015-04-24 no assertion criteria provided clinical testing
Natera, Inc. RCV000984308 SCV002092287 pathogenic Niemann-Pick disease, type A 2017-03-17 no assertion criteria provided clinical testing

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