rs750294638
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_000165.5(GJA1):c.605G>A(p.Arg202His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000165.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.605G>A | p.Arg202His | missense_variant | Exon 2 of 2 | ENST00000282561.4 | NP_000156.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GJA1 | ENST00000282561.4 | c.605G>A | p.Arg202His | missense_variant | Exon 2 of 2 | 1 | NM_000165.5 | ENSP00000282561.3 | ||
GJA1 | ENST00000647564.1 | c.605G>A | p.Arg202His | missense_variant | Exon 2 of 2 | ENSP00000497565.1 | ||||
GJA1 | ENST00000649003.1 | c.605G>A | p.Arg202His | missense_variant | Exon 2 of 2 | ENSP00000497283.1 | ||||
GJA1 | ENST00000650427.1 | c.605G>A | p.Arg202His | missense_variant | Exon 2 of 2 | ENSP00000497367.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461842Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2024 | Published functional studies demonstrate a damaging effect (PMID: 15879313); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 14729836, 15637728, 24434540, 16531323, 12457340, 18946008, 19338053, 24133447, 16891658, 18831677, 30638447, 33584802, 34630166, 32318302, 15879313) - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Oculodentodigital dysplasia Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Duke University Health System Sequencing Clinic, Duke University Health System | Apr 20, 2023 | - - |
Oculodentodigital dysplasia, autosomal recessive Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 30, 2020 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change leads to intracellular retention, reduced gap junction plaque formation and impaired coupling (PMID: 15879313, 16531323). This variant has been reported in several individuals affected with oculodentodigital dysplasia (PMID: 12457340, 18946008). ClinVar contains an entry for this variant (Variation ID: 372744). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with histidine at codon 202 of the GJA1 protein (p.Arg202His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at