Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000352.6(ABCC8):āc.1067A>Gā(p.Tyr356Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,614,014 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y356Y) has been classified as Likely benign.
ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a helix (size 43) in uniprot entity ABCC8_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000352.6
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.943
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 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. 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. -
Uncertain significance, criteria provided, single submitter
clinical testing
New York Genome Center
Feb 23, 2022
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
May 03, 2022
Variant summary: ABCC8 c.1067A>G (p.Tyr356Cys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251460 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (4e-05 vs 0.0034), allowing no conclusion about variant significance. c.1067A>G has been reported in the literature in individuals affected with hyperglycemia, or impaired glucose tolerance. These reports do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. One experimental study showed that single KATP channels incorporating SUR1-Y356C displayed lower sensitivity to MgATP. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Likely benign n=1, VUS n=4). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Hereditary hyperinsulinism Uncertain:1
Uncertain significance, no assertion criteria provided
clinical testing
Natera, Inc.
Sep 16, 2020
- -
Monogenic diabetes Uncertain:1
Uncertain significance, criteria provided, single submitter
research
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Sep 23, 2016
ACMG Criteria:PP3, PS3 (functional evidence PMID 18346985). Notes: Family study showed one child of the proband with impaired glucose intolerance and the variant and another child of the same proband with normal glucose tolerance and the variant in PMID 22210575 -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Athena Diagnostics
Jul 06, 2018
- -
Permanent neonatal diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Diabetes mellitus, transient neonatal, 2 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 28, 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. -