rs547150342

Variant names:

• chr11-17412700-C-T
• rs547150342
• NM_000352.6:c.2522G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000352.6(ABCC8):​c.2522G>A​(p.Arg841Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,924 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R841G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ABCC8 NM_000352.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1 O:2
• Conservation: PhyloP100: 7.89
• Publications: 0 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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-17412701-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1489024.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-17412700-C-T is Pathogenic according to our data. Variant chr11-17412700-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554121.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCC8	NM_000352.6	c.2522G>A	p.Arg841Gln	missense_variant	Exon 21 of 39	ENST00000389817.8	NP_000343.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCC8	ENST00000389817.8	c.2522G>A	p.Arg841Gln	missense_variant	Exon 21 of 39	1	NM_000352.6	ENSP00000374467.4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152020 Hom.: 0 Cov.: 32

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: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247266 AF XY: 0.00000749

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459786 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725882

African (AFR) AF: 0.00 AC: 0 AN: 33436

American (AMR) AF: 0.00 AC: 0 AN: 44532

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111072

Other (OTH) AF: 0.00 AC: 0 AN: 60302

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74384

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2110

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hyperinsulinemic hypoglycemia, familial, 1 Pathogenic:2 Uncertain:1

Jan 13, 2020

Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NM_000352.6:c.2522G>A variant is not present in publicly available database, Exome Variant Server (EVS). The variant is present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a very low frequency (MAF<=0.0001) in heterozygous state. The variant is not present in our in-house exome database. The variant was earlier reported to Human Genome Mutation database (HGMD ID: CM112697) in other similarly affected individuals [Banerjee et al., Eur J Endocrinol 2011]. In-silico pathogenicity prediction programs like SIFT, Polyphen2, MutationTaster2, CADD etc. predicted this variant as likely deleterious. Hence as per ACMG guidelines the variant has been classified as likely pathogenic. -

Sep 26, 2017

Counsyl

Significance: Uncertain significance

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. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial hyperinsulinism Pathogenic:1

Jun 24, 2025

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCC8 c.2522G>A (p.Arg841Gln) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.2522G>A has been observed at a heterozygous state, paternally inherited, in one individual affected with diazoxide-unresponsive congenital hyperinsulinism and loss of maternal heterozygosity was noted in the pancreatic tissue (Banerjee_2011), and was also reported at a compound heterozygous with a second pathogenic variant in an individual affected with autosomal recessive ABCC8-associated hyperinsulinism (Stringer_2024). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. At least one variant at the Arg841 residue has been reported as Likely Pathogenic (p.Arg841Gly), suggesting that this codon is functionally important. These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21378087, 39153498). ClinVar contains an entry for this variant (Variation ID: 554121). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Type 2 diabetes mellitus Pathogenic:1

May 20, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

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

Mar 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 13, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 841 of the ABCC8 protein (p.Arg841Gln). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg841 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 11395395, 32202736), which suggests that this may be a clinically significant amino acid residue. 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: 554121). This variant is also known as c.2525G>A p.Arg842Gln. This missense change has been observed in individuals with clinical features of autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 21378087, 24686051). This variant is not present in population databases (gnomAD no frequency). -

Neonatal diabetes mellitus Other:1

May 27, 2024

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain risk allele

Review Status: criteria provided, single submitter

Collection Method: research

This variant is found to be a potent moderate impact, variant with a CADD score of 29.8 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele. -

Maturity onset diabetes mellitus in young Other:1

May 29, 2024

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Uncertain risk allele

Review Status: criteria provided, single submitter

Collection Method: research

Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant ( rs547150342) in MODY yet. This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.8 and sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	.;.;M;.;.;.;.;.
PhyloP100		7.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;D;.;.;.;.
Polyphen		0.99	.;.;D;.;.;.;.;.
Vest4		0.97, 0.97
MutPred		0.99		.;.;Loss of MoRF binding (P = 0.0178);.;.;.;Loss of MoRF binding (P = 0.0178);.;
MVP		0.98
MPC		0.97
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.97
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs547150342; hg19: chr11-17434247; COSMIC: COSV105132390;