rs193922297

Variant names:

• chr7-44150990-A-G
• rs193922297
• NM_000162.5:c.449T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-44150990-A-G
• chr7-44150990-A-T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM5 PP2 PP3 PM2_Supporting PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The c.449T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 150 (p.(Phe150Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.0.0 Popmax filtering allele frequency of 0 (below the MDEP threshold of 0.000003), and ≤ 2 copies observed in the European non-Finnish population and any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in at least 28 unrelated individuals with hyperglycemia (PS4; PMIDs: 15305805, 30191644, internal lab contributors). This variant segregated with hyperglycemia, with at least 19 informative meioses in multiple families (PP1_Strong; internal lab contributors). Another missense variant, c.449T>A p.Phe150Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Ser has a greater Grantham distance (PM5). In summary, c.449T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PS4, PP1_Strong, PM2_Supporting, PP3, PP2, PM5. LINK:https://erepo.genome.network/evrepo/ui/classification/CA213784/MONDO:0015967/086

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GCK NM_000162.5 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.25
• Publications: 18 publications found

Genes affected

GCK (HGNC:4195): (glucokinase) This gene encodes a member of the hexokinase family of proteins. Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. In contrast to other forms of hexokinase, this enzyme is not inhibited by its product glucose-6-phosphate but remains active while glucose is abundant. The use of multiple promoters and alternative splicing of this gene result in distinct protein isoforms that exhibit tissue-specific expression in the pancreas and liver. In the pancreas, this enzyme plays a role in glucose-stimulated insulin secretion, while in the liver, this enzyme is important in glucose uptake and conversion to glycogen. Mutations in this gene that alter enzyme activity have been associated with multiple types of diabetes and hyperinsulinemic hypoglycemia. [provided by RefSeq, Aug 2017]

GCK Gene-Disease associations (from GenCC):

• hyperinsulinism due to glucokinase deficiency

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• maturity-onset diabetes of the young type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• permanent neonatal diabetes mellitus 1

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• transient neonatal diabetes mellitus

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• permanent neonatal diabetes mellitus

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300758 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCK	NM_000162.5	c.449T>C	p.Phe150Ser	missense_variant	Exon 4 of 10	ENST00000403799.8	NP_000153.1
GCK	NM_033507.3	c.452T>C	p.Phe151Ser	missense_variant	Exon 4 of 10		NP_277042.1
GCK	NM_033508.3	c.446T>C	p.Phe149Ser	missense_variant	Exon 5 of 11		NP_277043.1
GCK	NM_001354800.1	c.449T>C	p.Phe150Ser	missense_variant	Exon 4 of 11		NP_001341729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCK	ENST00000403799.8	c.449T>C	p.Phe150Ser	missense_variant	Exon 4 of 10	1	NM_000162.5	ENSP00000384247.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Maturity-onset diabetes of the young type 2 Pathogenic:2

Jun 28, 2023

Genetics and Molecular Pathology, SA Pathology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GCK c.449T>C variant is classified as Likely Pathogenic (PS4_Moderate, PM2_Supporting, PS3_Supporting, PP3, PP4_Moderate). The GCK c.449T>C variant is a single nucleotide change in exon 4/10 of the GCK gene, which is predicted to change the amino acid phenylalanine at position 150 in the protein to serine. The variant has been reported multiple times in the literature in unrelated affected individuals with a clinical presentation of MODY (PMID: 30191644, 14517946, 9662401, 34789499) (PS4_Moderate). This variant is absent from population databases (PM2_Supporting). A yeast hybrid complementation functional study completed by Gersing et al, 2013 demonstrated a reduction in human GCK activity with this variant compared to non-pathogenic GCK variants/ WT control (PMID: 37101203, PS3_Supporting). Computational predictions support a deleterious effect on the gene or gene product (PP3). The clinical features of this case are highly specific for the GCK gene, the family history is consistent with the mode of inheritance of this condition and this patient has a well-defined syndrome with little overlap with other clinical presentations (PP4_Moderate). The variant has been reported in dbSNP (rs193922297) and in the HGMD database as disease causing (CM980893). It has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 36218). -

Aug 18, 2011

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

- -

Monogenic diabetes Pathogenic:1

Mar 22, 2024

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.449T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 150 (p.(Phe150Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.0.0 Popmax filtering allele frequency of 0 (below the MDEP threshold of 0.000003), and <=2 copies observed in the European non-Finnish population and any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). This variant was identified in at least 28 unrelated individuals with hyperglycemia (PS4; PMIDs: 15305805, 30191644, internal lab contributors). This variant segregated with hyperglycemia, with at least 19 informative meioses in multiple families (PP1_Strong; internal lab contributors). Another missense variant, c.449T>A p.Phe150Tyr has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Ser has a greater Grantham distance (PM5). In summary, c.449T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PS4, PP1_Strong, PM2_Supporting, PP3, PP2, PM5. -

not provided Pathogenic:1

Jan 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed 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: 30191644, 9662401, 14517946, 14517956, 18271687, 32533152, 32041611, 15305805) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;D;.;.;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D;.;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-8.0	.;D;D;D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.99
MutPred		0.98		.;Gain of disorder (P = 0.0172);.;.;.;
MVP		0.96
MPC		2.9
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs193922297; hg19: chr7-44190589;