rs376074787
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP6
The NM_000165.5(GJA1):āc.814T>Cā(p.Ser272Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000477 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJA1 | NM_000165.5 | c.814T>C | p.Ser272Pro | 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.814T>C | p.Ser272Pro | missense_variant | Exon 2 of 2 | 1 | NM_000165.5 | ENSP00000282561.3 | ||
GJA1 | ENST00000647564.1 | c.814T>C | p.Ser272Pro | missense_variant | Exon 2 of 2 | ENSP00000497565.1 | ||||
GJA1 | ENST00000649003.1 | c.814T>C | p.Ser272Pro | missense_variant | Exon 2 of 2 | ENSP00000497283.1 | ||||
GJA1 | ENST00000650427.1 | c.814T>C | p.Ser272Pro | missense_variant | Exon 2 of 2 | ENSP00000497367.1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251476Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135908
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461816Hom.: 0 Cov.: 33 AF XY: 0.0000495 AC XY: 36AN XY: 727218
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
GJA1-related disorder Uncertain:1
The GJA1 c.814T>C variant is predicted to result in the amino acid substitution p.Ser272Pro. This variant was reported in an infant with sudden death syndrome; however, pathogenicity was not established (Van Norstrand et al. 2012. PubMed ID: 22179534; Klaver et al. 2011. PubMed ID: 21215473). Functional studies indicated that the p.Ser272Pro variant did not disrupt trafficking and maintained wildtype levels of junctional conductance (Van Norstrand et al. 2012. PubMed ID: 22179534). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-121768807-T-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:1
Has been previously reported as heterozygous in a 3 month old infant from a cohort of cases of sudden infant death; an in vitro study indicated that this variant did not appear to affect protein trafficking (PMID: 22179534); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21215473, 22179534, 23103513, 23304551, 31043699, 23465283, 15192806) -
Oculodentodigital dysplasia, autosomal recessive Uncertain:1
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 272 of the GJA1 protein (p.Ser272Pro). This variant is present in population databases (rs376074787, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GJA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 580391). 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) has been performed 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 GJA1 protein function. Experimental studies have shown that this missense change does not substantially affect GJA1 function (PMID: 22179534). 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. -
Hypoplastic left heart syndrome 1 Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Oculodentodigital dysplasia Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Syndactyly type 3 Benign:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at