Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS1_Very_StrongPM1PM2PP3_StrongPP5_Moderate
The NM_000352.6(ABCC8):c.4432G>C(p.Gly1478Arg) 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. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G1478G) 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]
Our verdict: Pathogenic. The variant received 18 ACMG points.
PS1
Transcript NM_000352.6 (ABCC8) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 434045
PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000352.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant 11-17394379-C-G is Pathogenic according to our data. Variant chr11-17394379-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 3233553.Status of the report is criteria_provided_single_submitter, 1 stars.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: ABCC8 c.4432G>C (p.Gly1478Arg) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251454 control chromosomes (gnomAD). p.Gly1478Arg has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism or early onset diabetes (e.g. Pinney_2008, Delvecchio_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 18596924, 28323911). No submitters have cited clinical-significance assessments for c.4432G>C to ClinVar, although another nucleotide change resulting in the same missense alteration (c.4432G>A/p.Gly1478Arg, Variation ID: 434045) is classified as pathogenic by our lab. Based on the evidence outlined above, the variant was classified as pathogenic. -