11-17395914-C-T

Position:

chr11-17395914-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000352.6(ABCC8):c.4136G>A(p.Arg1379His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,585,350 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. R1379C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.91

Variant links:

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]

ABCC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 2 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 chr11-17395915-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9105.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 11-17395914-C-T is Pathogenic according to our data. Variant chr11-17395914-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 585346.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 linkuse as main transcript	c.4136G>A	p.Arg1379His	missense_variant	34/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8 linkuse as main transcript	c.4136G>A	p.Arg1379His	missense_variant	34/39	1	NM_000352.6	P4	Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1433152

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

709692

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000274

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 17, 2022	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4136G>A, in exon 34 that results in an amino acid change, p.Arg1379His. The p.Arg1379His change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Arg1379His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the Ashkenazi Jewish subpopulation (dbSNP rs193922401). This sequence change has been previously described in multiple individual and affected family members with neonatal diabetes/monogenic diabetes (PMID: 17446535, 21989597, 24622368, 33300273, 29207974, 22210575, 23093687, 27271189, 19342262, 17446535, 17389331). Additionally, other missense changes at this same position (p. Arg1379Cys, p. Arg1379Pro, p.Arg1379Leu, p. Arg1379Ser) have been reported in individuals with ABCC8-related diabetes (PMID: 16885549, 24622368, 27681997, 24622368, 18025408). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively. -

ABCC8-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 10, 2023

The ABCC8 c.4136G>A variant is predicted to result in the amino acid substitution p.Arg1379His. This variant has been reported multiple times in individuals with neonatal diabetes (including, but not limited to Flanagan et al. 2007. PubMed ID: 17446535; Bowman et al. 2011. PubMed ID: 21989597; Riveline et al. 2011. PubMed ID: 22210575 ). Different variants that affect this same amino acid residue (p.Arg1379Leu, p.Arg1379Ser, and p.Arg1379Cys) have been reported in association with disease (Rafiq et al. 2008. PubMed ID: 18025408; Bennett et al. 2015. PubMed ID: 25555642; Babenko et al. 2006. PubMed ID: 16885549), suggesting the p.Arg1379 is a critical residue for typical protein function. This variant is interpreted as likely pathogenic. -

Monogenic diabetes

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 22, 2020

The p.Arg1379His (sometimes called p.Arg1380His) variant in ABCC8 has been reported in 12 individuals with Monogenic Diabetes and segregated with disease in 5 affected relatives from 2 families (PMID: 22210575, 23093687, 27271189, 21989597, 19342262, 17446535, 17389331; DOI: 10.1016/j.clinph.2015.04.103). Data from large population studies is insufficient to assess the frequency of this variant. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 585346). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional variants, each with a different amino acid change at the same position, (p.Arg1379Leu, p.Arg1379Ser, and p.Arg1379Cys), have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 18025464; Variation ID: 9105, 35614, 35615). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PP1_Moderate, PP3, PS4_moderate (Richards 2015). -

Maturity onset diabetes mellitus in young

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 19, 2022

Variant summary: ABCC8 c.4136G>A (p.Arg1379His) 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 allele was found at a frequency of 1.5e-05 in 201446 control chromosomes. c.4136G>A has been reported in the literature in multiple individuals affected with Neonatal Diabetes Mellitus/Maturity Onset Diabetes Of The Young in an autosomal dominant manner (example: Bowman_2012, Flannagan_2007 and Bonfanti_2021). These data indicate that the variant is very likely to be associated with disease. Additional variants at the same position have been associated with NDM/MODY and related conditions in ClinVar and HGMD (R1379C, R1379L, R1379P, R1379S). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

D;.;D;D;D;D;D;D

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.89

Polyphen

1.0

.;.;D;.;.;.;.;.

Vest4

0.97, 0.97

MutPred

0.96

.;.;Loss of methylation at R1379 (P = 0.0249);.;.;.;Loss of methylation at R1379 (P = 0.0249);.;

MVP

0.96

MPC

2.0

ClinPred

0.98

GERP RS

5.1

Varity_R

0.92

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over