18-22200789-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_005257.6(GATA6):c.1754G>A(p.Arg585Gln) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R585L) has been classified as Uncertain significance.
Frequency
Consequence
NM_005257.6 missense
Scores
Clinical Significance
Conservation
Publications
- atrial septal defect 9Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Ambry Genetics
- atrioventricular septal defect 5Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
- GATA6-related congenital heart disease with or without pancreatic agenesis or neonatal diabetesInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- pancreatic hypoplasia-diabetes-congenital heart disease syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- metabolic syndromeInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- neonatal diabetes mellitusInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- tetralogy of fallotInheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
- familial atrial fibrillationInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- conotruncal heart malformationsInheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Uncertain_significance. The variant received 4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GATA6 | ENST00000269216.10 | c.1754G>A | p.Arg585Gln | missense_variant | Exon 7 of 7 | 1 | NM_005257.6 | ENSP00000269216.3 | ||
GATA6 | ENST00000581694.1 | c.1754G>A | p.Arg585Gln | missense_variant | Exon 6 of 6 | 1 | ENSP00000462313.1 | |||
ENSG00000266283 | ENST00000583442.1 | n.600C>T | non_coding_transcript_exon_variant | Exon 2 of 2 | 3 | |||||
ENSG00000266283 | ENST00000822675.1 | n.198C>T | non_coding_transcript_exon_variant | Exon 1 of 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Atrioventricular septal defect 5 Uncertain:1
This sequence change replaces arginine with glutamine at codon 585 of the GATA6 protein (p.Arg585Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GATA6-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at