NM_000352.6(ABCC8):c.1973G>T (p.Gly658Val) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: May 31, 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:: RCV002506852.7

Allele description [Variation Report for NM_000352.6(ABCC8):c.1973G>T (p.Gly658Val)]

NM_000352.6(ABCC8):c.1973G>T (p.Gly658Val)

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.1973G>T (p.Gly658Val)

HGVS:

NC_000011.10:g.17428356C>A
NG_008867.1:g.53547G>T
NM_000352.6:c.1973G>TMANE SELECT
NM_001287174.3:c.1973G>T
NM_001351295.2:c.2039G>T
NM_001351296.2:c.1970G>T
NM_001351297.2:c.1970G>T
NP_000343.2:p.Gly658Val
NP_001274103.1:p.Gly658Val
NP_001338224.1:p.Gly680Val
NP_001338225.1:p.Gly657Val
NP_001338226.1:p.Gly657Val
LRG_790t1:c.1973G>T
LRG_790t2:c.1973G>T
LRG_790:g.53547G>T
LRG_790p1:p.Gly658Val
LRG_790p2:p.Gly658Val
NC_000011.9:g.17449903C>A
NM_000352.3:c.1973G>T
NM_000352.4:c.1973G>T
NR_147094.2:n.2039G>T

Protein change:

G657V

Links:

dbSNP: rs149400972

NCBI 1000 Genomes Browser:

rs149400972

Molecular consequence:

NM_000352.6:c.1973G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001287174.3:c.1973G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351295.2:c.2039G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351296.2:c.1970G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001351297.2:c.1970G>T - missense variant - [Sequence Ontology: SO:0001583]
NR_147094.2:n.2039G>T - 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
SCV002817254	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (Mar 10, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003482036	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 26, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31595705, 28492532
SCV003930963	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 31, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002817254

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Uncertain significance
(Mar 10, 2021)

unknown

clinical testing

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

SCV003482036

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 26, 2022)

germline

clinical testing

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

SCV003930963

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 31, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

Targeted sequencing identifies novel variants in common and rare MODY genes.

de Santana LS, Caetano LA, Costa-Riquetto AD, Franco PC, Dotto RP, Reis AF, Weinert LS, Silveiro SP, Vendramini MF, do Prado FA, Abrahão GCP, de Almeida AGFP, Tavares MDGR, Gonçalves WRB, Santomauro Junior AC, Halpern B, Jorge AAL, Nery M, Teles MG.

Mol Genet Genomic Med. 2019 Dec;7(12):e962. doi: 10.1002/mgg3.962. Epub 2019 Oct 8.

PubMed [citation]

PMID:: 31595705
PMCID:: PMC6900361

See all PubMed Citations (3)

Details of each submission

From Athena Diagnostics, SCV002817254.1

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

Description

This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003482036.1

#	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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 658 of the ABCC8 protein (p.Gly658Val). This variant is present in population databases (rs149400972, gnomAD 0.02%). This missense change has been observed in individual(s) with ABCC8-related conditions (PMID: 31595705). ClinVar contains an entry for this variant (Variation ID: 1337205). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 GeneDx, SCV003930963.1

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

Description

Observed in an individual with early-onset diabetes in published literature (de Santana et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34014594, 31595705)

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

Last Updated: Sep 29, 2024

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