rs121918410
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000171.4(GLRA1):c.920A>G(p.Tyr307Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y307S) has been classified as Pathogenic.
Frequency
Consequence
NM_000171.4 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 |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.920A>G | p.Tyr307Cys | missense_variant | 8/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.920A>G | p.Tyr307Cys | missense_variant | 8/9 | ||
GLRA1 | NM_001292000.2 | c.671A>G | p.Tyr224Cys | missense_variant | 7/8 | ||
GLRA1 | XM_047417105.1 | c.968A>G | p.Tyr323Cys | missense_variant | 8/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.920A>G | p.Tyr307Cys | missense_variant | 8/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.920A>G | p.Tyr307Cys | missense_variant | 8/9 | 1 | A1 | ||
GLRA1 | ENST00000462581.6 | c.*678A>G | 3_prime_UTR_variant, NMD_transcript_variant | 7/8 | 1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Hyperekplexia 1 Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1995 | - - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Oct 04, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Prenatal Diagnosis Center, The First Affiliated Hospital of Zhengzhou University | May 13, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 05, 2021 | - - |
Hereditary hyperekplexia Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 10, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 307 of the GLRA1 protein (p.Tyr307Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant hyperekplexia (PMID: 7611730, 11389164; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16063). 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 GLRA1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 9009272). This variant disrupts the p.Tyr307 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been observed in individuals with GLRA1-related conditions (PMID: 16236274), which suggests that this may be a clinically significant amino acid residue. 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