rs769569410
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000352.6(ABCC8):c.928G>A(p.Asp310Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,792 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. D310V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000352.6 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 |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.928G>A | p.Asp310Asn | missense_variant | 6/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.928G>A | p.Asp310Asn | missense_variant | 6/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250942Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135748
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461566Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727108
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
Type 2 diabetes mellitus Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | DASA | Jun 10, 2022 | The c.928G>A;p.(Asp310Asn) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 585352; PMID: 27908292; 27188453; 23275527; 21536946; 20427569; 18596924) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 20427569) - PS3_supporting. The variant is present at low allele frequencies population databases (rs769569410– gnomAD 0.00006569%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) -PM2_supporting. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is Likely Pathogenic - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 22, 2023 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 20, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 310 of the ABCC8 protein (p.Asp310Asn). This variant is present in population databases (rs769569410, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital hyperinsulinism and type 2 diabetes (PMID: 16429405, 18596924, 27188453, 33046911). ClinVar contains an entry for this variant (Variation ID: 585352). Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18596924, 20427569). 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 ABCC8 protein function. This variant disrupts the p.Asp310 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 17236890; Invitae), which suggests that this may be a clinically significant amino acid residue. 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. - |
Hereditary hyperinsulinism Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 25, 2021 | - - |
Type 2 diabetes mellitus;C0271714:Leucine-induced hypoglycemia;C1835887:Diabetes mellitus, transient neonatal, 2;C2931832:Hyperinsulinemic hypoglycemia, familial, 1;C5394303:Diabetes mellitus, permanent neonatal 3 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Aug 16, 2023 | The p.Asp310Asn variant in ABCC8 has been previously reported in 3 individuals with hyperinsulinemic hypoglycemia (PMID: 16429405, 17236890, 27908292) and has been seen in 0.006% (2/34590) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs769569410). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 585352) and has been interpreted as likely pathogenic by Fulgent Genetics, DASA, Natera Inc, Athena Diagnostics Inc, and Invitae. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Asp310Asn variant is pathogenic (PMID: 17236890). In vitro functional studies provide some evidence that the p.Asp310Asn variant may slightly impact protein function (PMID: 18596924, 20427569). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3, PP3, PM2, PS3_supporting (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at