chr11-17395918-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000352.6(ABCC8):c.4132G>A(p.Gly1378Ser) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1378R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.4132G>A | p.Gly1378Ser | missense_variant | 34/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.4132G>A | p.Gly1378Ser | missense_variant | 34/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1430714Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 708366
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 14, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1378 of the ABCC8 protein (p.Gly1378Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital hyperinsulinism (CHI) (PMID: 34304300). This variant has been reported in individual(s) with autosomal dominant ABCC8-related conditions (PMID: 24401662, 24814349, 36504295); however, the role of the variant in this condition is currently unclear. This variant is also known as c.4135G>A (p.Gly1379Ser). ClinVar contains an entry for this variant (Variation ID: 1338261). 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. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 24814349). This variant disrupts the p.Gly1378 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16357843, 23275527). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 17, 2023 | Observed in the heterozygous state and with a second ABCC8 variant in individuals affected with hyperinsulinism; in one patient, the variant inherited from mother affected with diffuse hyperinsulinism (Mohnike et al., 2014; Dung et al., 2013; Ponzi et al., 2018; Panigrahy et al., 2022; Yorifuji et al., 2023); Observed in a patient diagnosed with diffuse congenital hyperinsulinism in published literature; variant inherited from unaffected father, and authors conclude the variant is likely recessive and the patient likely had misdiagnosed focal hyperinsulinism, rather than diffuse (Saint-Martin et al., 2015); Published functional studies demonstrate a damaging effect on protein trafficking (Saint-Martin et al., 2015); Not observed in large population cohorts (gnomAD); Also known as c.4135G>A p.G1379S; This variant is associated with the following publications: (PMID: 24814349, : 36504295, 30193751, 24401662, 34304300) - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 03, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at