rs1554935669
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_000543.5(SMPD1):āc.1730A>Gā(p.His577Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,614,054 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H577Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000543.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SMPD1 | NM_000543.5 | c.1730A>G | p.His577Arg | missense_variant | 6/6 | ENST00000342245.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SMPD1 | ENST00000342245.9 | c.1730A>G | p.His577Arg | missense_variant | 6/6 | 1 | NM_000543.5 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461888Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727244
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74334
ClinVar
Submissions by phenotype
Niemann-Pick disease, type A Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 29, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Niemann-Pick disease, type A;C0268243:Niemann-Pick disease, type B Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 16, 2022 | This missense change has been observed in individual(s) with Niemann-Pick disease (PMID: 20386867, 34273913). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 577 of the SMPD1 protein (p.His577Arg). ClinVar contains an entry for this variant (Variation ID: 550112). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His577 amino acid residue in SMPD1. Other variant(s) that disrupt this residue have been observed in individuals with SMPD1-related conditions (PMID: 12712061, 20386867, 26499107), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects SMPD1 function (PMID: 20386867). 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. - |
Likely pathogenic, criteria provided, single submitter | research | Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS | Apr 25, 2021 | - - |
Sphingomyelin/cholesterol lipidosis Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 28, 2023 | Variant summary: SMPD1 c.1730A>G (p.His577Arg) results in a non-conservative amino acid change located in the Sphingomyelin phosphodiesterase, C-terminal domain (IPR045473) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251448 control chromosomes (gnomAD). c.1730A>G has been reported in the literature in compound heterozygous and homozygous individuals affected with Niemann-Pick Disease (Desnick_2010, Deshpande_2021). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and p.H577R had less than 1% of expressed wild-type activity (Desnick_2010). The following publications have been ascertained in the context of this evaluation (PMID: 34273913, 20386867, 27435900). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=1, likely pathogenic (n=3) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 03, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at