NM_000171.4:c.896G>A
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000171.4(GLRA1):c.896G>A(p.Arg299Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,774 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R299L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000171.4 missense
Scores
Clinical Significance
Conservation
Publications
- hyperekplexia 1Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- hereditary hyperekplexiaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000171.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLRA1 | NM_000171.4 | MANE Select | c.896G>A | p.Arg299Gln | missense | Exon 7 of 9 | NP_000162.2 | ||
| GLRA1 | NM_001146040.2 | c.896G>A | p.Arg299Gln | missense | Exon 7 of 9 | NP_001139512.1 | |||
| GLRA1 | NM_001292000.2 | c.647G>A | p.Arg216Gln | missense | Exon 6 of 8 | NP_001278929.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLRA1 | ENST00000274576.9 | TSL:1 MANE Select | c.896G>A | p.Arg299Gln | missense | Exon 7 of 9 | ENSP00000274576.5 | ||
| GLRA1 | ENST00000455880.2 | TSL:1 | c.896G>A | p.Arg299Gln | missense | Exon 7 of 9 | ENSP00000411593.2 | ||
| GLRA1 | ENST00000462581.6 | TSL:1 | n.*654G>A | non_coding_transcript_exon | Exon 6 of 8 | ENSP00000430595.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460774Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726782 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Hyperekplexia 1 Pathogenic:9
This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.01 (v4: 1 heterozygote(s), 0 homozygote(s)); This variant has strong previous evidence of pathogenicity in unrelated individuals. Also known as p.(Arg271Gln) in the literature, at least ten patients with dominant hyperekplexia 1 (MIM#149400) have been reported to harbour this variant (ClinVar, PMID: 11389164, 14673895, 25356525, 28122427); This variant has strong evidence for segregation with disease. It has been shown to segregate in a large 3-generation family with nine affecteds (PMID: 11389164); Variant is located in a hotspot region or cluster of pathogenic variants within the pore-forming M2 transmembrane domain (DECIPHER; PMID: 25356525); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a minor amino acid change. Additional information: Variant is predicted to result in a missense amino acid change from arginine to glutamine; This variant is heterozygous; This gene is associated with both recessive and dominant disease. Autosomal recessive (AR) variants are located throughout the gene while autosomal dominant (AD) variants are mostly located within the TM2-Loop2 domains (PMID: 32319239); Loss of function is a known mechanism of disease in this gene and is associated with hyperekplexia 1 (MIM#149400). Dominant negative has also been suggested for a single variant (PMID: 17536053); Variants in this gene are known to have variable expressivity. In a single AR family with two affected brothers, one was more severely affected than the other (PMID: 30866851); This variant has been shown to be paternally inherited by paternal segregation analysis.
The p.Arg299Gln variant (also known as p.Arg271Gln) identified in this individual has been reported in multiple patients affected with autosomal dominant hyperekplexia/startle syndrome, and co-segregates with autosomal dominant hyperekplexia in several families [PMID: 8298642; PMID: 8733061; PMID: 28138086]. The variant is absent from the gnomAD database indicating it is an extremely rare allele in the general population. The variant affects a highly conserved residue and is predicted deleterious by in silico tools. Functional studies have found that the mutant allele results in reduced glycinergic inhibitory neurotransmission by the glycine receptor-channel complex [PMID: 7518444]. Moreover, a different missense variant affecting the same Arg299 of GLRA1 has also been reported in several affected individuals [PMID: 8298642; PMID: 7881416].Based on the available evidence, the p.Arg299Gln variant in the GLRA1 gene is assessed as pathogenic.
The observed missense variant c.896G>Ap.Arg299Gln in GLRA1 gene has been reported previously in individuals with autosomal dominant hyperekplexia, also known as startle syndrome. Experimental studies have shown that this missense change affects GLRA1 function. This variant is present in a mutational hotspot. A different missense change p.Arg299Leu affecting the same position has been reported as Likely pathogenic Russo SP, et al., 2017; Paucar M, et al., 2018; Rajendra S, et al., 1994; Shiang R, et al., 1993. This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic by multiple submitters. The amino acid Arg at position 299 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Criteria applied: PS2,PS3,PS4,PM5_STR,PM1,PM2_SUP,PP3,PP4
PS3_Supporting, PS4, PM2, PM6, PP1_Moderate, PP3
Inborn genetic diseases Pathogenic:1
The c.896G>A (p.R299Q) alteration is located in exon 7 (coding exon 7) of the GLRA1 gene. This alteration results from a G to A substitution at nucleotide position 896, causing the arginine (R) at amino acid position 299 to be replaced by a glutamine (Q). for autosomal dominant GLRA1-related hyperekplexia; however, its clinical significance for autosomal recessive GLRA1-related hyperekplexia is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant, also referred to as p.R271Q, was reported in multiple individuals with features consistent with autosomal dominant GLRA1-related hyperekplexia and segregated with disease in at least one family; in one instance, this variant was determined to be the result of a de novo mutation (Shiang, 1993; Schorderet, 1994; Elmslie, 1996; Kwok, 2001; Tijssen, 2003; Lee, 2017; Mariani, 2017; Pavey, 2017; Russo, 2017; Paucar, 2018). Another alteration at the same codon, c.896G>T (p.R299L), has been detected in at least one individual with features consistent with autosomal dominant GLRA1-related hyperekplexia (Shiang, 1993). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
not provided Pathogenic:1
Published functional studies demonstrate this variant impairs chloride channel activation and conductance (Langosch et al., 1994; Moraga-Cid et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9009272, 7881416, 1355335, 1897565, 6830476, 7826634, 7925268, 30109271, 25730860, 8298642, 28122427)
Hereditary hyperekplexia Pathogenic:1
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 299 of the GLRA1 protein (p.Arg299Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hyperekplexia, also known as startle syndrome (PMID: 8298642, 8733061, 28122427, 28138086). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16061). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLRA1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GLRA1 function (PMID: 7518444). This variant disrupts the p.Arg299 amino acid residue in GLRA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881416, 8298642). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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