rs137852673

chr11-17395915-G-Achr11-17395915-G-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.4135C>T(p.Arg1379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,432,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 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. R1379H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.57

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, 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 chr11-17395914-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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 11-17395915-G-A is Pathogenic according to our data. 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCC8	NM_000352.6	c.4135C>T	p.Arg1379Cys	missense_variant	34/39	ENST00000389817.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCC8	ENST00000389817.8	c.4135C>T	p.Arg1379Cys	missense_variant	34/39	1	NM_000352.6	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000497 AC: 1 AN: 201102 Hom.: 0 AF XY: 0.00000930 AC XY: 1 AN XY: 107540

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000329

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432938 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709572

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000241

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

ExAC AF: 0.00000834 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

Diabetes mellitus, transient neonatal, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 27, 2007

- -

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.Arg1379Cys (sometimes called p.Arg1380Cys) variant in ABCC8 has been reported in 7 individuals with Monogenic Diabetes, segregated with disease in 4 affected relatives from 1 family (PMID: 16885549, 17446535, 25306193), and has been identified in 0.003286% (1/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Trio analysis showed this variant to be de novo with unconfirmed maternity and paternity in one individual reported in the literature (PMID: 17446535). This variant has also been reported pathogenic in ClinVar (Variation ID: 9105). In vitro functional studies provide some evidence that the p.Arg1379Cys variant may slightly increase the rate of ATP hydrolysis (PMID: 18025464). However, these types of assays may not accurately represent biological function. 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 with a different amino acid change at the same position, (p.Arg1379His, p.Arg1379Leu and p.Arg1379Ser), have been reported in association with disease in ClinVar or have been curated likely pathogenic or as variants of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615, 35614). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM6, PM5_supporting, PS3_supporting, PM2_Supporting, PP3, PS4_Supporting, PP1 (Richards 2015). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 24, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1379 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 17446535), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18025464). 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. ClinVar contains an entry for this variant (Variation ID: 9105). This variant is also known as R1380C. This missense change has been observed in individuals with autosomal dominant ABCC8-related early onset diabetes (PMID: 16885549, 17446535, 27681997). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1379 of the ABCC8 protein (p.Arg1379Cys). -

Permanent neonatal diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.80	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	Pathogenic	0.91	D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.96, 0.97
MutPred		0.97		.;.;Loss of disorder (P = 0.0172);.;.;.;Loss of disorder (P = 0.0172);.;
MVP		0.94
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.89

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: rs137852673; hg19: chr11-17417462; COSMIC: COSV56856915; COSMIC: COSV56856915;