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NM_000162.5(GCK):c.787T>C (p.Ser263Pro) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 5, 2022
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:
RCV002467500.4

Allele description [Variation Report for NM_000162.5(GCK):c.787T>C (p.Ser263Pro)]

NM_000162.5(GCK):c.787T>C (p.Ser263Pro)

Gene:
GCK:glucokinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7p13
Genomic location:
Preferred name:
NM_000162.5(GCK):c.787T>C (p.Ser263Pro)
HGVS:
  • NC_000007.14:g.44147726A>G
  • NG_008847.2:g.55445T>C
  • NM_000162.5:c.787T>CMANE SELECT
  • NM_001354800.1:c.787T>C
  • NM_033507.3:c.790T>C
  • NM_033508.3:c.784T>C
  • NP_000153.1:p.Ser263Pro
  • NP_001341729.1:p.Ser263Pro
  • NP_277042.1:p.Ser264Pro
  • NP_277043.1:p.Ser262Pro
  • LRG_1074t1:c.787T>C
  • LRG_1074t2:c.790T>C
  • LRG_1074:g.55445T>C
  • LRG_1074p1:p.Ser263Pro
  • LRG_1074p2:p.Ser264Pro
  • NC_000007.13:g.44187325A>G
  • NM_000162.3:c.787T>C
  • NM_033508.1:c.784T>C
  • p.SER263PRO
  • p.Ser262Pro
Protein change:
S262P
Links:
dbSNP: rs193922331
NCBI 1000 Genomes Browser:
rs193922331
Molecular consequence:
  • NM_000162.5:c.787T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354800.1:c.787T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033507.3:c.790T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_033508.3:c.784T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Type 2 diabetes mellitus
Synonyms:
DIABETES MELLITUS, TYPE 2, PROTECTION AGAINST; Type II diabetes mellitus; Diabetes mellitus, noninsulin-dependent, late onset
Identifiers:
MONDO: MONDO:0005148; MeSH: D003924; MedGen: C0011860; OMIM: 125853; Human Phenotype Ontology: HP:0005978
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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002764498New York Genome Center
criteria provided, single submitter

(NYGC Assertion Criteria 2020)		Likely pathogenic
(Jan 5, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing

Details of each submission

From New York Genome Center, SCV002764498.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the exon 7 of GCK gene has been reported in multiple patients with hyperglycemia and found to be co-segregated with disease phenotype [PMID: 22820548, 16731834, 32074423] and was reported as pathogenic in a cohort study involving hypertriglyceridemia and familial hypercholesterolemia patients [PMID: 32041611]. In vitro functional studies demonstrated that p. Ser263Pro variant leads to protein misfolding, thermal instability and aberrant dimerization [PMID:22820548,16731834]. The variant has 0.000006570 allele frequency in the gnomAD(v3) database (1 out of 152218 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The identified variant has been reported in the ClinVar database as a Likely Pathogenic [Variation ID: 36258]. The variant affects a moderately conserved residue in the large hexokinase domain of the GCK protein [PMID: 31638168] and is predicted deleterious by multiple in silico tools (CADD score = 22.7, REVEL score = 0.689). Based on the available evidence, the heterozygous c.787T>C (p.Ser263Pro) missense variant identified in the GCK gene is classified as ‘Likely Pathogenic’.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Oct 13, 2024