rs199547699
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_000171.4(GLRA1):c.277C>T(p.Arg93Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,590 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. R93L) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLRA1 | NM_000171.4 | c.277C>T | p.Arg93Trp | missense_variant | 4/9 | ENST00000274576.9 | |
GLRA1 | NM_001146040.2 | c.277C>T | p.Arg93Trp | missense_variant | 4/9 | ||
GLRA1 | NM_001292000.2 | c.28C>T | p.Arg10Trp | missense_variant | 3/8 | ||
GLRA1 | XM_047417105.1 | c.325C>T | p.Arg109Trp | missense_variant | 4/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRA1 | ENST00000274576.9 | c.277C>T | p.Arg93Trp | missense_variant | 4/9 | 1 | NM_000171.4 | P4 | |
GLRA1 | ENST00000455880.2 | c.277C>T | p.Arg93Trp | missense_variant | 4/9 | 1 | A1 | ||
GLRA1 | ENST00000471351.2 | n.560C>T | non_coding_transcript_exon_variant | 4/8 | 1 | ||||
GLRA1 | ENST00000462581.6 | c.*35C>T | 3_prime_UTR_variant, NMD_transcript_variant | 3/8 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251370Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135886
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461392Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727038
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74412
ClinVar
Submissions by phenotype
Hyperekplexia 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Hereditary hyperekplexia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 04, 2022 | ClinVar contains an entry for this variant (Variation ID: 225379). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg93 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been observed in individuals with GLRA1-related conditions (PMID: 20631190), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 20631190, 24108130). 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. This variant is also known as R65W. This missense change has been observed in individuals with autosomal recessive hyperekplexia (PMID: 20631190, 24108130). This variant is present in population databases (rs199547699, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 93 of the GLRA1 protein (p.Arg93Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at