11-17395664-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000352.6(ABCC8):c.4253G>A(p.Arg1418His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,408,704 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R1418C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.91

Genes affected

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000352.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17395665-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1338454.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 11-17395664-C-T is Pathogenic according to our data. Variant chr11-17395664-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 552540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4253G>A	p.Arg1418His	missense_variant	35/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4253G>A	p.Arg1418His	missense_variant	35/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1408704 Hom.: 0 Cov.: 31 AF XY: 0.00000431 AC XY: 3 AN XY: 695636

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000250

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000277

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 23, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1418 of the ABCC8 protein (p.Arg1418His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 15579781, 23275527, 25720052). This variant is also known as R1419H. ClinVar contains an entry for this variant (Variation ID: 552540). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 23798684). This variant disrupts the p.Arg1419 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 24401662, 26316440), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2022	Also known as p.R1419H; Published functional studies demonstrate a severe trafficking defect that results in a loss of potassium channel function (Tornovsky et al., 2004; Harel et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25781536, 23798684, 25720052, 34304300, 23275527, 23226049, 23345197, 15579781, 34631896) -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 14, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 28, 2022

- -

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 14, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.98, 0.98
MutPred		0.97		.;.;Loss of methylation at R1418 (P = 0.0175);.;.;.;Loss of methylation at R1418 (P = 0.0175);.;
MVP		0.98
MPC		2.0
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.95
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1446306735; hg19: chr11-17417211; COSMIC: COSV100217047; COSMIC: COSV100217047;