NM_000352.6(ABCC8):c.4181T>G (p.Met1394Arg) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Nov 21, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003553966.2

Allele description [Variation Report for NM_000352.6(ABCC8):c.4181T>G (p.Met1394Arg)]

NM_000352.6(ABCC8):c.4181T>G (p.Met1394Arg)

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.4181T>G (p.Met1394Arg)

HGVS:

NC_000011.10:g.17395869A>C
NG_008867.1:g.86034T>G
NM_000352.6:c.4181T>GMANE SELECT
NM_001287174.3:c.4184T>G
NM_001351295.2:c.4247T>G
NM_001351296.2:c.4181T>G
NM_001351297.2:c.4178T>G
NP_000343.2:p.Met1394Arg
NP_001274103.1:p.Met1395Arg
NP_001338224.1:p.Met1416Arg
NP_001338225.1:p.Met1394Arg
NP_001338226.1:p.Met1393Arg
LRG_790t1:c.4181T>G
LRG_790t2:c.4184T>G
LRG_790:g.86034T>G
LRG_790p1:p.Met1394Arg
LRG_790p2:p.Met1395Arg
NC_000011.9:g.17417416A>C
NR_147094.2:n.4476T>G

Protein change:

M1393R

Molecular consequence:

NM_000352.6:c.4181T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.4184T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.4247T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.4181T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.4178T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.4476T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004295376	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23266803, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004295376

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 21, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Co-inheritance of two ABCC8 mutations causing an unresponsive congenital hyperinsulinism: clinical and functional characterization of two novel ABCC8 mutations.

Faletra F, Snider K, Shyng SL, Bruno I, Athanasakis E, Gasparini P, Dionisi-Vici C, Ventura A, Zhou Q, Stanley CA, Burlina A.

Gene. 2013 Mar 1;516(1):122-5. doi: 10.1016/j.gene.2012.12.055. Epub 2012 Dec 22.

PubMed [citation]

PMID:: 23266803
PMCID:: PMC3600632

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004295376.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1394 of the ABCC8 protein (p.Met1394Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 23266803). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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: 23266803). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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