rs120074117
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000543.5(SMPD1):c.1493G>A(p.Arg498His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,614,126 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R498C) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.1493G>A | p.Arg498His | missense_variant | 6/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.1493G>A | p.Arg498His | missense_variant | 6/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251078Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135702
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461882Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727240
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74424
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 22, 2023 | ClinVar contains an entry for this variant (Variation ID: 167712). This variant is also known as c.1487G>A, p.R496H. This missense change has been observed in individuals with Niemann-Pick disease (PMID: 15221801, 27338287, 31965297, 32292456; Invitae). This variant is present in population databases (rs120074117, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 498 of the SMPD1 protein (p.Arg498His). 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. For these reasons, this variant has been classified as Pathogenic. 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). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 18, 2022 | - - |
Niemann-Pick disease, type A Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 11, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Apr 25, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 08, 2014 | - - |
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.Arg498His variant in SMPD1 (also known as p.Arg496His due to a difference in cDNA numbering) has been reported in at least 2 individuals with Niemann-Pick disease (PMID: 27338287, 15221801) and has been identified in 0.007% (2/30614) of South Asian chromosomes and 0.001% (1/113412) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs120074117). 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. 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 an affected homozygote and in combination with a reported pathogenic variant in an individual with Niemann-Pick disease increases the likelihood that the p.Arg498His variant is pathogenic (VariationID: 167710; PMID: 27338287, 15221801). The phenotype of an individual compound heterozygous for this variant is highly specific for Niemann-Pick disease based on acid sphingomyelinase activity being <10% of normal, consistent with disease (PMID: 27338287). Multiple variants in the same region as p.Arg498His 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: 2980, 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.Arg498Cys 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, 198095; PMID: 29995201, 18815062, 15221801, 27338287, 25834946, 23356216). 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). - |
Abnormality of metabolism/homeostasis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at