11-17395918-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.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:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• 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 5 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 chr11-17395918-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 554195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 11-17395918-C-T is Pathogenic according to our data. Variant chr11-17395918-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1338261.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-17395918-C-T is described in UniProt as null.

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: 0 AN: 1430714 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 708366

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.90	D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.93, 0.93
MutPred		0.91		.;.;Gain of catalytic residue at G1378 (P = 0.0266);.;.;.;Gain of catalytic residue at G1378 (P = 0.0266);.;
MVP		0.96
MPC		1.8
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.98
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs925231098; hg19: chr11-17417465;