VCV002137006.3 - ClinVar

NM_000352.6(ABCC8):c.4532T>C (p.Ile1511Thr)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(2)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000352.6(ABCC8):c.4532T>C (p.Ile1511Thr)

Variation ID: 2137006 Accession: VCV002137006.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.1 11: 17394279 (GRCh38) [ NCBI UCSC ] 11: 17415826 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 8, 2023	Feb 14, 2024	Dec 8, 2021

HGVS

Nucleotide	Protein	Molecular consequence
NM_000352.6:c.4532T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000343.2:p.Ile1511Thr	missense
NM_000352.4:c.4532T>C
NM_001287174.3:c.4535T>C	NP_001274103.1:p.Ile1512Thr	missense
NM_001351295.2:c.4598T>C	NP_001338224.1:p.Ile1533Thr	missense
NM_001351296.2:c.4532T>C	NP_001338225.1:p.Ile1511Thr	missense
NM_001351297.2:c.4529T>C	NP_001338226.1:p.Ile1510Thr	missense
NR_147094.2:n.4827T>C		non-coding transcript variant
NC_000011.10:g.17394279A>G
NC_000011.9:g.17415826A>G
NG_008867.1:g.87624T>C
LRG_790:g.87624T>C
LRG_790t1:c.4532T>C	LRG_790p1:p.Ile1511Thr
LRG_790t2:c.4535T>C	LRG_790p2:p.Ile1512Thr

... more HGVS ... less HGVS

Protein change

I1510T, I1511T, I1512T, I1533T

Other names

Canonical SPDI

NC_000011.10:17394278:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCC8		-	-	GRCh38 GRCh37	2370	2502

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 8, 2021	RCV003062338.3
Hyperinsulinemic hypoglycemia, familial, 1	Likely pathogenic (1)	no assertion criteria provided	-	RCV003227081.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Dec 08, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003439614.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (1) PubMed: 18596924 Comment: 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) … (more) 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile1511 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18596924). This variant is also known as p.I1512T. This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism (PMID: 18596924). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1511 of the ABCC8 protein (p.Ile1511Thr). (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	Hyperinsulinemic hypoglycemia, familial, 1 Affected status: yes Allele origin: maternal	Department of Endocrinology, Genetics and Metabolism, Shanghai Children's Medical Center Accession: SCV003922074.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023

Comment:

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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile1511 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 18596924). This variant is also known as p.I1512T. This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism (PMID: 18596924). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1511 of the ABCC8 protein (p.Ile1511Thr).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical characteristics and biochemical mechanisms of congenital hyperinsulinism associated with dominant KATP channel mutations.	Pinney SE	The Journal of clinical investigation	2008	PMID: 18596924

Text-mined citations for this variant ...

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000352.6(ABCC8):c.4532T>C (p.Ile1511Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...