rs201682634

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000352.6(ABCC8):c.220C>T(p.Arg74Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 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. R74Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ABCC8
NM_000352.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 8.04

Publications

16 publications found

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 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)

ABCC8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 4 uncertain in NM_000352.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-17474955-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 495834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.92

PP5

Variant 11-17474956-G-A is Pathogenic according to our data. Variant chr11-17474956-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371380.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 link	c.220C>T	p.Arg74Trp	missense_variant	Exon 2 of 39	ENST00000389817.8	NP_000343.2	Q09428-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8 link	c.220C>T	p.Arg74Trp	missense_variant	Exon 2 of 39	1	NM_000352.6	ENSP00000374467.4		Q09428-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000796

AC:

AN:

251388

AF XY:

0.0000147

show subpopulations

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:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1112000

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000720

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1

Pathogenic:2

Sep 16, 2016

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:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg74Trp variant in ABCC8 has been reported in 9 individuals with hyperinsulinemic hypoglycemia (PMID: 14692646, 14715863, 16357843, 16429405, 20432820, 23345197, 26740944, 24645945, 25518065), and has been identified in 0.002% (3/129106) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs201682634). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 371380) and has been interpreted as pathogenic/likely pathogenic by Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Fulgent Genetics, Natera (Inc.), and Counsyl. Of the 9 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg74Trp variant is pathogenic (PMID: 14692646, 16357843, 20432820). In vitro functional studies provide some evidence that the p.Arg74Trp variant may slightly impact protein function (PMID: 17575084). 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. One additional pathogenic variant, resulting in a different amino acid change at the same position, (p.Arg74Gln), has been reported in association with disease in the literature/ClinVar, supporting that a change at this position may not be tolerated (PMID: 9618169, 10338089, 10828824, 20685672, 23275527, 23345197, 28701683, 30352420, 36239000/Variation ID: 495834). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PM2_supporting, PS3_supporting, PP3, PM5 (Richards 2015). -

Familial hyperinsulinism

Pathogenic:1

Apr 21, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ABCC8 c.220C>T (p.Arg74Trp) results in a non-conservative amino acid change in 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 8e-06 in 251388 control chromosomes (gnomAD). c.220C>T has been reported in the literature in heterozygous state in multiple patients affected with focal- (or unspecified) Congenital Hyperinsulinism (CHI), as well as in patients with diffuse CHI (Suchi_2003, Fernandez-Marmiesse_2006, Senniappan_2014, Fan_2015), and in at least one case affected with diffuse HI, the presence of another pathogenic variant (R1215Q) in trans was indicated (Suchi_2003). Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated strongly reduced cell surface expression (Yan_2007, Pratt_2009, Pratt_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Type 2 diabetes mellitus

Pathogenic:1

Dec 13, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary hyperinsulinism

Pathogenic:1

Aug 18, 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

Jan 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCC8-related disorder

Pathogenic:1

Jan 24, 2024

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

The c.220C>T (p.Arg74Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. This variant has been previously reported as a heterozygous and compound heterozygous change in patients with hyperinsulinemic hypoglycemia and late adolescence/adult-onset diabetes (PMID: 14692646, 19151370, 24645945, 25518065, 31291970). Different amino acid changes at the same residue (p.Arg74Gln, p.Arg74Leu) have been previously reported in individuals with hyperinsulinemic hypoglycemia and early-onset diabetes (PMID: 9618169, 27810688, 30352420, 33046911, 36239000, 32027066). Multiple functional studies have demonstrated this variant to have a deleterious effect on the protein cell surface expression, stability, and function (PMID: 17575084, 19151370, 21321069). The c.220C>T (p.Arg74Trp) variant is present in the heterozygous state in the gnomAD v4 population database at a frequency of 0.0005% (9/1614174), and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, c.220C>T (p.Arg74Trp) is classified as Pathogenic. -

not provided

Pathogenic:1

Jul 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Experimental studies have shown that this missense change affects ABCC8 function (PMID: 17575084, 19151370, 21321069). 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: 371380). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 14692646, 16429405, 24645945, 25518065). This variant has been reported in individual(s) with autosomal dominant hyperinsulinemic hypoglycemia (PMID: 24645945); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (rs201682634, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 74 of the ABCC8 protein (p.Arg74Trp). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

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

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

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

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.92

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.4

.;M;M;M;.;.;.;.

PhyloP100

8.0

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.8

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

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.96, 0.96

MVP

0.98

MPC

0.94

ClinPred

1.0

GERP RS

5.2

Varity_R

0.89

gMVP

0.88

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over