rs200670692

Variant names:

• chr11-17476715-A-T
• rs200670692
• NM_000352.6:c.62T>A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_000352.6(ABCC8):​c.62T>A​(p.Val21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,609,238 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V21F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 9.04
• Publications: 10 publications found

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 Gene-Disease associations (from GenCC):

• hyperinsulinemic hypoglycemia, familial, 1

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• diabetes mellitus, permanent neonatal 3

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• familial hyperinsulinism

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• diabetes mellitus

  Inheritance: SD Classification: DEFINITIVE Submitted by: Ambry Genetics
• monogenic diabetes

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypoglycemia, leucine-induced

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• transient neonatal diabetes mellitus

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• permanent neonatal diabetes mellitus

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• diabetes mellitus, transient neonatal, 2

  Inheritance: Unknown, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• pulmonary arterial hypertension

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• autosomal dominant hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• DEND syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diazoxide-resistant focal hyperinsulinism due to SUR1 deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive hyperinsulinism due to SUR1 deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• type 2 diabetes mellitus

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000287898 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 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, 8 uncertain in NM_000352.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17476716-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3014266.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872
• PP5: Variant 11-17476715-A-T is Pathogenic according to our data. Variant chr11-17476715-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 495835.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.62T>A	p.Val21Asp	missense_variant	Exon 1 of 39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.62T>A	p.Val21Asp	missense_variant	Exon 1 of 39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151752 Hom.: 0 Cov.: 33

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000582 AC: 14 AN: 240646 AF XY: 0.0000305

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000476

Gnomad NFE exome AF: 0.000121

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000350 AC: 51 AN: 1457486 Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 724920

African (AFR) AF: 0.00 AC: 0 AN: 33246

American (AMR) AF: 0.00 AC: 0 AN: 44372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85510

European-Finnish (FIN) AF: 0.0000190 AC: 1 AN: 52650

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1110244

Other (OTH) AF: 0.00 AC: 0 AN: 60208

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151752 Hom.: 0 Cov.: 33 AF XY: 0.0000405 AC XY: 3 AN XY: 74112

African (AFR) AF: 0.00 AC: 0 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10564

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67906

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000378 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000991 AC: 12

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2

Mar 11, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 16, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Val21Asp variant in ABCC8 has been reported in at least 6 individuals with hyperinsulinemic hypoglycemia (PMID: 16357843, 19475716, 20685672, 23345197, 23275527), and has been identified 0.011% (14/122860) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200670692). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 495835) and has been interpreted as pathogenic/likely pathogenic by Invitae, Natera Inc., Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Counsyl and Fulgent Genetics. Of the many affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, and 1 was a homozygote, which increases the likelihood that the p.Val21Asp variant is pathogenic (Variation ID: 633026; PMID: 16357843, 19475716, 20685672, 23345197, 23275527). In vitro functional studies provide some evidence that the p.Val21Asp variant may slightly impact protein function (PMID: 27573238). 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. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PP3, PS3_supporting (Richards 2015). -

Familial hyperinsulinism Pathogenic:1

Feb 23, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The ABCC8 c.62T>A (p.Val21Asp) variant causes a missense change involving the alteration of a conserved nucleotide. Although the variant is located outside of any known functional domain of the ATP-regulated potassium channels, 5/5 in silico tools predict a deleterious outcome for this variant. This variant was found in 12/88122 control chromosomes at a frequency of 0.0001362, which does not exceed the estimated maximal expected allele frequency of a pathogenic ABCC8 variant (0.0033541). Furthermore, this variant was identified homozygously or in compound heterozygosity in multiple diazoxide-unresponsive comprehensively genotyped neonatal patients with biochemically and histologically confirmed diagnosed diffuse CHI which is inherited in an autosomal recessive manner. Although no in-vitro functional studies supporting a loss of function of the ATP regulated potassium channels have been reported, the available patient characteristics provide in-vivo evidence demonstrating a damaging effect of this variant on channel function. Taken together, the ascertained evidence has been weighted to classify this variant as Pathogenic. -

Type 2 diabetes mellitus Pathogenic:1

Feb 04, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hyperinsulinism Pathogenic:1

Apr 30, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Oct 15, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ABCC8-related disorder Pathogenic:1

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported as homozygous and compound heterozygous change in patients with congenital hyperinsulinemic hypoglycemia (PMID: 23345197, 19475716). The c.62T>A (p.Val21Asp) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (15/271858) and is absent in the homozygous state, thus is presumed to be rare. The c.62T>A (p.Val21Asp) variant affects a moderately conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.62T>A (p.Val21Asp) variant is classified as Pathogenic. -

not provided Pathogenic:1

Jul 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 21 of the ABCC8 protein (p.Val21Asp). This variant is present in population databases (rs200670692, gnomAD 0.01%). This missense change has been observed in individuals with recessive congenital hyperinsulinism (PMID: 19475716, 20685672, 23345197). ClinVar contains an entry for this variant (Variation ID: 495835). 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: 27573238). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	30
DANN	Uncertain	0.98
DEOGEN2	Benign	0.39	.;.;T;.;.;.;.;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Uncertain	2.3	.;M;M;M;.;.;.;.;M
PhyloP100		9.0
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.0	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;D;.;.;.;.;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.
Vest4		0.87, 0.88, 0.99
MVP		0.96
MPC		1.1
ClinPred		0.75	D
GERP RS		3.0
PromoterAI		0.082	Neutral
Varity_R		0.92
gMVP		0.95
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs200670692; hg19: chr11-17498262;