NM_000162.5(GCK):c.556C>T (p.Arg186Ter) AND Maturity-onset diabetes of the young type 2

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 4, 2024
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:: RCV002225072.8

Allele description [Variation Report for NM_000162.5(GCK):c.556C>T (p.Arg186Ter)]

NM_000162.5(GCK):c.556C>T (p.Arg186Ter)

Gene:

GCK:glucokinase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7p13

Genomic location:

Preferred name:

NM_000162.5(GCK):c.556C>T (p.Arg186Ter)

HGVS:

NC_000007.14:g.44149992G>A
NG_008847.2:g.53179C>T
NM_000162.5:c.556C>TMANE SELECT
NM_001354800.1:c.556C>T
NM_033507.3:c.559C>T
NM_033508.3:c.553C>T
NP_000153.1:p.Arg186Ter
NP_001341729.1:p.Arg186Ter
NP_277042.1:p.Arg187Ter
NP_277043.1:p.Arg185Ter
LRG_1074t1:c.556C>T
LRG_1074t2:c.559C>T
LRG_1074:g.53179C>T
LRG_1074p1:p.Arg186Ter
LRG_1074p2:p.Arg187Ter
NC_000007.13:g.44189591G>A
NM_000162.3:c.556C>T
p.ARG186*

Protein change:

R185*; ARG186TER

Links:

OMIM: 138079.0002; dbSNP: rs104894006

NCBI 1000 Genomes Browser:

rs104894006

Molecular consequence:

NM_000162.5:c.556C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354800.1:c.556C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033507.3:c.559C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_033508.3:c.553C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Maturity-onset diabetes of the young type 2
Synonyms:: MODY type 2; Diabetes mellitus MODY type 2; MODY glucokinase-related; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007453; MedGen: C0342277; Orphanet: 552; OMIM: 125851

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002503627	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 23, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1360036, 8094163, 9049484, 15841481, 25741868
SCV002562178	Geisinger Clinic, Geisinger Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2022)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 36257325
SCV005050209	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Mar 4, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 1360036, 8068341, 8094163, 8096296, 15841481, 17573900, 18271687, 36504295 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002503627

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 23, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002562178

Geisinger Clinic, Geisinger Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 2, 2022)

germline

research

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

SCV005050209

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Mar 4, 2024)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families.

Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, Passa P, Deschamps I, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P.

Diabetologia. 1997 Feb;40(2):217-24.

PubMed [citation]

PMID:: 9049484

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

See all PubMed Citations (11)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV002503627.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature termination codon at position 186 in exon 5 (of 10) of GCK (p.Arg186*). It is expected to result in an absent or disrupted protein product (PVS1). Loss of function is an established mechanism of disease for GCK-associated disease. The variant is absent in a large population cohort (rs104894006, gnomAD v2.1 - PM2). It has been identified heterozygous in at least two probands diagnosed with maturity-onset diabetes of the young (MODY, PMID: 9049484, 15841481 - PS4_Supporting), and segregates with MODY or late-onset non-insulin-dependent diabetes mellitus (NIDDM) in multiple affected individuals in at least two families (PMID: 1360036, 8094163 - PP1_Strong). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PP1_Strong, PM2, PS4_Supporting.

#	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

From Geisinger Clinic, Geisinger Health System, SCV002562178.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	research	PubMed (2)

Description

PVS1, PM2, PP1_Strong, PS4, PP4

#	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		5	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005050209.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: GCK c.556C>T (p.Arg186X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD v2.1 is considered unreliable, as metrics indicate poor data quality at this position. However, the variant was found at a frequency of 6.8e-6 in 1461654 chromosomes in gnomAD v4.0. c.556C>T has been reported in the literature in individuals affected with Maturity Onset Diabetes Of The Young (e.g. Yorifuji_2023). The following publications have been ascertained in the context of this evaluation (PMID: 1360036, 15841481, 8068341, 8094164, 8094163, 8096296, 17573900, 18271687, 36504295). ClinVar contains an entry for this variant (Variation ID: 16133). 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

Last Updated: Jul 29, 2024

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