rs397514677
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001382567.1(STIM1):āc.326A>Gā(p.His109Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 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 Pathogenic (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H109N) has been classified as Pathogenic.
Frequency
Consequence
NM_001382567.1 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
STIM1 | NM_001382567.1 | c.326A>G | p.His109Arg | missense_variant | 3/13 | ENST00000526596.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
STIM1 | ENST00000526596.2 | c.326A>G | p.His109Arg | missense_variant | 3/13 | 5 | NM_001382567.1 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727216
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2024 | STIM1: PM2, PM5, PM6, PS4:Moderate, PP4, PS3:Supporting - |
Myopathy, tubular aggregate, 1 Pathogenic:2
Likely pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2014 | - - |
Myopathy with tubular aggregates;C1861451:Stormorken syndrome;C2748557:Combined immunodeficiency due to STIM1 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 109 of the STIM1 protein (p.His109Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tubular aggregate myopathy (TAM) (PMID: 23332920, 24570283). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 41483). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STIM1 protein function. Experimental studies have shown that this missense change affects STIM1 function (PMID: 23332920). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at