rs145136257
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_000352.6(ABCC8):c.1063G>A(p.Ala355Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000699 in 1,613,994 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A355A) has been classified as Likely benign.
Frequency
Consequence
NM_000352.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ABCC8 | NM_000352.6 | c.1063G>A | p.Ala355Thr | missense_variant | 7/39 | ENST00000389817.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ABCC8 | ENST00000389817.8 | c.1063G>A | p.Ala355Thr | missense_variant | 7/39 | 1 | NM_000352.6 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000579 AC: 88AN: 152114Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000461 AC: 116AN: 251468Hom.: 0 AF XY: 0.000375 AC XY: 51AN XY: 135912
GnomAD4 exome AF: 0.000711 AC: 1040AN: 1461880Hom.: 1 Cov.: 31 AF XY: 0.000670 AC XY: 487AN XY: 727244
GnomAD4 genome ? AF: 0.000579 AC: 88AN: 152114Hom.: 1 Cov.: 32 AF XY: 0.000485 AC XY: 36AN XY: 74288
ClinVar
Submissions by phenotype
not provided Uncertain:7
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Aug 30, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 25, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Identified in the heterozygous state in a patient with permanent neonatal diabetes and a patient with congenital hyperinsulinism (Russo et al., 2011; Kapoor et el., 2013), and observed in the heterozygous state with a second variant in cis in a patient with congenital hyperinsulinism (Ismail et al., 2011); however, also observed in the heterozyous state in many unaffected, unrelated individuals referred for genetic testing at GeneDx; This variant is associated with the following publications: (PMID: 31604004, 20943779, 23345197, 21544516) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 355 of the ABCC8 protein (p.Ala355Thr). This variant is present in population databases (rs145136257, gnomAD 0.09%). This missense change has been observed in individual(s) with congenital hyperinsulinism or persistent neonatal diabetes mellitus (PMID: 20943779, 21544516, 24401662, 27908292, 28442472). ClinVar contains an entry for this variant (Variation ID: 210066). 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 not expected to disrupt ABCC8 protein function. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 02, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 06, 2023 | Variant summary: ABCC8 c.1063G>A (p.Ala355Thr) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251468 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00046 vs 0.0034), allowing no conclusion about variant significance. c.1063G>A has been reported in the literature in individuals affected with Congenital Hyperinsulinism without strong evidence of causality (e.g. Hussain_2005, Snider_2013, Kapoor_2013, Mohnike_2014, Li_2017, Ismail_2011). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. Co-occurrences with another pathogenic variant in cis has been reported (ABCC8 c.4477C>T, p.Arg1493Trp, Ismail_2011), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16186397, 23275527, 23345197, 24401662, 28442472, 36407475, 20943779). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Hyperinsulinemic hypoglycemia, familial, 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Type 2 diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Mar 05, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 29, 2021 | The c.1063G>A (p.A355T) alteration is located in exon 7 (coding exon 7) of the ABCC8 gene. This alteration results from a G to A substitution at nucleotide position 1063, causing the alanine (A) at amino acid position 355 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Hereditary hyperinsulinism Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 19, 2021 | - - |
Diabetes mellitus, transient neonatal, 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Permanent neonatal diabetes mellitus Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at