VCV000036205.6 - ClinVar

NM_000162.5(GCK):c.175C>T (p.Pro59Ser)

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.

(4)

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/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000162.5(GCK):c.175C>T (p.Pro59Ser)

Variation ID: 36205 Accession: VCV000036205.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p13 7: 44153334 (GRCh38) [ NCBI UCSC ] 7: 44192933 (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	Apr 4, 2013	Feb 14, 2024	Sep 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000162.5:c.175C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000153.1:p.Pro59Ser	missense
NM_001354800.1:c.175C>T	NP_001341729.1:p.Pro59Ser	missense
NM_033507.3:c.178C>T	NP_277042.1:p.Pro60Ser	missense
NM_033508.3:c.172C>T	NP_277043.1:p.Pro58Ser	missense
NC_000007.14:g.44153334G>A
NC_000007.13:g.44192933G>A
NG_008847.2:g.49837C>T
LRG_1074:g.49837C>T
LRG_1074t1:c.175C>T	LRG_1074p1:p.Pro59Ser
LRG_1074t2:c.178C>T	LRG_1074p2:p.Pro60Ser

... more HGVS ... less HGVS

Protein change

P59S, P60S, P58S

Other names

Canonical SPDI

NC_000007.14:44153333:G:A

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA213767 dbSNP: rs193922287 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.
GCK		-	-	GRCh38 GRCh37	1091	1117

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.
Maturity-onset diabetes of the young type 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 18, 2011	RCV000029868.2
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Sep 26, 2023	RCV000518012.6

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 (Jun 27, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613414.1 First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017	Publications: PubMed (4) PubMed: 22060211‚ 22335469‚ 26287533‚ 24804978
Pathogenic (Sep 26, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004169483.1 First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22060211, 26287533, 24804978, 22335469, 36227502, 36504295) (less)
likely pathogenic (Aug 18, 2011)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: curation, clinical testing	MODY2 (autosomal unknown) Affected status: unknown, yes Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000052523.2 First in ClinVar: Apr 04, 2013 Last updated: Mar 28, 2022	Comment: Converted during submission to Likely pathogenic. Observation 1: Tissue: Blood Observation 2: Tissue: Blood Observation 3: Tissue: Blood Observation 4: Tissue: Blood Observation 5: Tissue: Blood
Pathogenic (Jul 30, 2022)	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: SCV003439957.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 22060211‚ 22335469 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36205). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22060211, 22335469). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs193922287, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 59 of the GCK protein (p.Pro59Ser). (less)

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22060211, 26287533, 24804978, 22335469, 36227502, 36504295)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 36205). This missense change has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 22060211, 22335469). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs193922287, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 59 of the GCK protein (p.Pro59Ser).

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
Identification and Clinical Characterization of Adult Patients with Multigenerational Diabetes Mellitus.	Ludovico O	PloS one	2015	PMID: 26287533
Molecular and clinical characterization of glucokinase maturity-onset diabetes of the young (GCK-MODY) in Japanese patients.	Kawakita R	Diabetic medicine : a journal of the British Diabetic Association	2014	PMID: 24804978
MODY type 2 P59S GCK mutant: founder effect in South of Italy.	Delvecchio M	Clinical genetics	2013	PMID: 22335469
Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus.	Yorifuji T	Pediatric diabetes	2012	PMID: 22060211

Text-mined citations for rs193922287 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000162.5(GCK):c.175C>T (p.Pro59Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs193922287 ...