NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter) AND Hyperinsulinemic hypoglycemia, familial, 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Aug 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001174850.2

Allele description [Variation Report for NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter)]

NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter)

Gene:

ABCC8:ATP binding cassette subfamily C member 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11p15.1

Genomic location:

Preferred name:

NM_000352.6(ABCC8):c.3107G>A (p.Trp1036Ter)

Other names:

NM_000352.6(ABCC8):c.3107G>A; p.Trp1036Ter

HGVS:

NC_000011.10:g.17406943C>T
NG_008867.1:g.74960G>A
NM_000352.6:c.3107G>AMANE SELECT
NM_001287174.3:c.3110G>A
NM_001351295.2:c.3173G>A
NM_001351296.2:c.3107G>A
NM_001351297.2:c.3104G>A
NP_000343.2:p.Trp1036Ter
NP_001274103.1:p.Trp1037Ter
NP_001338224.1:p.Trp1058Ter
NP_001338225.1:p.Trp1036Ter
NP_001338226.1:p.Trp1035Ter
LRG_790t1:c.3107G>A
LRG_790t2:c.3110G>A
LRG_790:g.74960G>A
LRG_790p1:p.Trp1036Ter
LRG_790p2:p.Trp1037Ter
NC_000011.9:g.17428490C>T
NM_000352.3:c.3107G>A
NM_000352.4:c.3107G>A
NR_147094.2:n.3256G>A

Protein change:

W1035*

Links:

dbSNP: rs755259997

NCBI 1000 Genomes Browser:

rs755259997

Molecular consequence:

NR_147094.2:n.3256G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000352.6:c.3107G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001287174.3:c.3110G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351295.2:c.3173G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351296.2:c.3107G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001351297.2:c.3104G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hyperinsulinemic hypoglycemia, familial, 1 (HHF1)
Synonyms:: HYPERINSULINISM, FAMILIAL, WITH PANCREATIC NESIDIOBLASTOSIS; HYPOGLYCEMIA, HYPERINSULINEMIC, OF INFANCY; NESIDIOBLASTOSIS OF PANCREAS; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009734; MedGen: C2931832; Orphanet: 276575; Orphanet: 276598; OMIM: 256450

Recent activity

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rps1702 40S ribosomal protein eS17 [Schizosaccharomyces pombe]
rps1702 40S ribosomal protein eS17 [Schizosaccharomyces pombe]
Gene ID:2539331

Gene
DC160933 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone rst101...
DC160933 Xenopus tropicalis embryo gastrula Xenopus tropicalis cDNA clone rst101f19 3', mRNA sequence
gi|119064642|gnl|dbEST|43335158|dbj 0933.1|

Nucleotide
CBST13174.rev NICHD_XGC_tropThy1 Xenopus tropicalis cDNA clone IMAGE:8932567 3',...
CBST13174.rev NICHD_XGC_tropThy1 Xenopus tropicalis cDNA clone IMAGE:8932567 3', mRNA sequence
gi|126548544|gnl|dbEST|45062412|gb| 053.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001338240	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004026532	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001338240

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 2, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV004026532

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 16, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A.

J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.

PubMed [citation]

PMID:: 23275527
PMCID:: PMC3565119

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338240.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: ABCC8 c.3107G>A (p.Trp1036X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250932 control chromosomes. c.3107G>A has been reported in the literature in individuals affected with Congenital Hyperinsulinism who displayed a focal histology although the exact parent of origin or zygosity was not specified (Snider_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV004026532.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The p.Trp1036Ter variant in ABCC8 has been reported in 4 individuals with hyperinsulinemic hypoglycemia (PMID: 23275527), and has been identified in 0.0009% (1/113312) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755259997). 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: 585343) and has been interpreted as Pathogenic by Athena Diagnostics Inc, Invitae, and Women's Health and Genetics/Laboratory Corporation of America, LabCorp. Of the 4 affected individuals, all were compound heterozygotes that carried a reported pathogenic variants in trans, which increases the likelihood that the p.Trp1036Ter variant is pathogenic (PMID: 23275527). This nonsense variant leads to a premature termination codon at position 1036, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PM2_supporting (Richards 2015).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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