rs769904764
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_ModeratePM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000543.5(SMPD1):c.1492C>T(p.Arg498Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R498H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.1492C>T | p.Arg498Cys | missense_variant | 6/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.1492C>T | p.Arg498Cys | missense_variant | 6/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 251044Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135700
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461862Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727226
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 09, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 18, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Apr 25, 2021 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 11, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 26, 2014 | - - |
SMPD1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 23, 2023 | The SMPD1 c.1492C>T variant is predicted to result in the amino acid substitution p.Arg498Cys. This variant has been reported in individuals with Niemann-Pick disease (reported as R496L in Simonaro et al. 2002. PubMed ID: 12369017; Zhang et al. 2013. PubMed ID: 23356216; Hu et al. 2021. PubMed ID: 33675270). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-6415433-C-T). This variant is interpreted as likely pathogenic. - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 498 of the SMPD1 protein (p.Arg498Cys). This variant is present in population databases (rs769904764, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Niemann-Pick disease (PMID: 12369017, 23356216; 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: 198095). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMPD1 protein function. This variant disrupts the p.Arg498 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1391960, 1885770, 2023926, 18815062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Sphingomyelin/cholesterol lipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg498Cys variant in SMPD1 (also known as p.Arg496Cys due to a difference in cDNA numbering) has been reported in at least 3 individuals with Niemann-Pick disease (PMID: 17011332, 25834946, 23356216) and has been identified in 0.003% (1/30612) of South Asian chromosomes and 0.002% (3/128792) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs769904764). 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: 198095) as likely pathogenic by EGL Genetic Diagnostics, Counsyl, and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with reported pathogenic variants in 2 individuals with Niemann-Pick disease increases the likelihood that the p.Arg498Cys variant is pathogenic (VariationID: 198095, 25834946; PMID: 17011332, 25834946). The phenotype of an individual homozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 23356216). Multiple variants in the same region as p.Arg498Cys have been reported in association with disease in ClinVar and the literature and the variant is located in a region of SMPD1 that is essential to protein folding and stability, suggesting that this variant is in a hot spot and functional domain and supports pathogenicity (VariationID: 2991, 198095; PMID: 18815062, 27725636; DOI: 10.1111/febs.13655). Two additional pathogenic and likely pathogenic variants, resulting in a different amino acid change at the same position, p.Arg498Leu and p.Arg498His, have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (VariationID: 2980, 167712; PMID: 29995201, 18815062, 15221801, 27338287, 26499107, 27725636). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PM5, PM1, PM3, PP3, PP4 (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at