VCV000009210.8 - ClinVar

NM_175914.5(HNF4A):c.763C>T (p.Gln255Ter)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Pathogenic

for Monogenic diabetes

Classification is based on the expert panel submission

Aug 2024 by ClinGen Monogenic Diabetes Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175914.5(HNF4A):c.763C>T (p.Gln255Ter)

Variation ID: 9210 Accession: VCV000009210.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44419813 (GRCh38) [ NCBI UCSC ] 20: 43048453 (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	Oct 10, 2018	Feb 15, 2026	Aug 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_175914.5:c.763C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_787110.2:p.Gln255Ter	nonsense
NM_000457.6:c.829C>T	NP_000448.3:p.Gln277Ter	nonsense
NM_001030003.3:c.763C>T	NP_001025174.1:p.Gln255Ter	nonsense
NM_001030004.3:c.763C>T	NP_001025175.1:p.Gln255Ter	nonsense
NM_001258355.2:c.808C>T	NP_001245284.1:p.Gln270Ter	nonsense
NM_001287182.2:c.754C>T	NP_001274111.1:p.Gln252Ter	nonsense
NM_001287183.2:c.754C>T	NP_001274112.1:p.Gln252Ter	nonsense
NM_001287184.2:c.754C>T	NP_001274113.1:p.Gln252Ter	nonsense
NM_178849.3:c.829C>T	NP_849180.1:p.Gln277Ter	nonsense
NM_178850.3:c.829C>T	NP_849181.1:p.Gln277Ter	nonsense
NC_000020.11:g.44419813C>T
NC_000020.10:g.43048453C>T
NG_009818.1:g.69013C>T
LRG_483:g.69013C>T
LRG_483t2:c.829C>T	LRG_483p2:p.Gln277Ter

... more HGVS ... less HGVS

Protein change

Q255*, Q270*, Q277*, Q252*

Other names

Q268*
NM_175914.5(HNF4A):c.763C>T
p.Gln255Ter

Canonical SPDI

NC_000020.11:44419812:C:T

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.

Links

ClinGen: CA120182 OMIM: 600281.0001 dbSNP: rs137853334 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.
HNF4A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	770	785

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 1	Pathogenic (1)	no assertion criteria provided	Sep 27, 2001	RCV000009790.6
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 4, 2026	RCV001659688.7
Monogenic diabetes	Pathogenic (1)	reviewed by expert panel	Aug 30, 2024	RCV004699115.1

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.	Expand all rows Collapse all rows 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 (Aug 30, 2024) C Contributing to aggregate classification	reviewed by expert panel (ClinGen Diabetes ACMG Specifications HNF4A V2.0.0)	Monogenic diabetes (Autosomal dominant inheritance)	ClinGen Monogenic Diabetes Variant Curation Expert Panel FDA Recognized Database Accession: SCV005201075.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c3388a6a-bb70-404d-9071-818cc4259294 Comment: show The c.763C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 255 (p.(Gln255Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and located in biologically relevant exon 7 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 8945471, 22060211, internal lab contributors). This variant was segregated with diabetes, with at least 33 informative meioses in three families (PP1_Strong; PMID: 8945471, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.763C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS4_moderate, PP1_strong, PP4, PM2_Supporting. (less) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Pathogenic (Apr 20, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (Athena Diagnostics criteria)	not provided	Athena Diagnostics Accession: SCV001880029.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021	Publications: PubMed (6) PubMed: 10606640‚ 10905494‚ 17389749‚ 30191603‚ 8945471‚ 9371825 Comment: show This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Q268X. This variant has been identified in at least one family with clinical features associated with this gene, where incomplete penetrance was noted (PMID: 8945471). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in the loss of transcriptional transactivation activity (PMID: 9371825). (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jan 04, 2026) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003443366.4 First in ClinVar: Feb 07, 2023 Last updated: Feb 15, 2026	Publications: PubMed (5) PubMed: 20164212‚ 23275527‚ 23348805‚ 24097065‚ 8945471 Comment: show This sequence change creates a premature translational stop signal (p.Gln255*) in the HNF4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF4A are known to be pathogenic (PMID: 20164212, 23275527, 23348805, 24097065). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HNF4A-related conditions (PMID: 8945471). This variant is also known as Q268X. ClinVar contains an entry for this variant (Variation ID: 9210). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Sep 27, 2001) N Not contributing to aggregate classification	no assertion criteria provided	MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 1	OMIM Accession: SCV000030011.4 First in ClinVar: Apr 04, 2013 Last updated: Oct 25, 2025	Publications: PubMed (2) PubMed: 11575290‚ 8945471 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: In the historic R-W pedigree in which Fajans (1989) defined type 1 maturity-onset diabetes of the young (MODY1; 125850), Yamagata et al. (1996) found a … (more) In the historic R-W pedigree in which Fajans (1989) defined type 1 maturity-onset diabetes of the young (MODY1; 125850), Yamagata et al. (1996) found a C-to-T substitution in codon 268 of the TCF14 gene that generated a CAG-to-TAG (Q268X) nonsense mutation. Some subjects in the R-W pedigree had inherited the Q268X mutation but were not yet diabetic; in addition, there were subjects in the pedigree who had noninsulin-dependent diabetes mellitus but did not inherit the Q268X mutation or at-risk haplotype. In one case, NIDDM had been diagnosed at the age of 48 years, and the patient was hyperinsulinemic, indicating that this was probably late-onset NIDDM rather than MODY. The patient had 6 children, 1 of whom also had NIDDM; another child had impaired glucose tolerance, and all had only normal alleles at the TCF14 locus. (less)

Comment:

The c.763C>T variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, results in a premature termination at codon 255 (p.(Gln255Ter)) of NM_175914.5. This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and located in biologically relevant exon 7 of 10, is predicted to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant was identified in five unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID: 8945471, 22060211, internal lab contributors). This variant was segregated with diabetes, with at least 33 informative meioses in three families (PP1_Strong; PMID: 8945471, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for HNF4A-MODY (MODY probability calculator result >50% and, negative genetic testing for HNF1A) (PP4; internal lab contributors). In summary, c.763C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PVS1, PS4_moderate, PP1_strong, PP4, PM2_Supporting.

Comment:

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as Q268X. This variant has been identified in at least one family with clinical features associated with this gene, where incomplete penetrance was noted (PMID: 8945471). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant results in the loss of transcriptional transactivation activity (PMID: 9371825).

Comment:

This sequence change creates a premature translational stop signal (p.Gln255*) in the HNF4A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF4A are known to be pathogenic (PMID: 20164212, 23275527, 23348805, 24097065). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with HNF4A-related conditions (PMID: 8945471). This variant is also known as Q268X. ClinVar contains an entry for this variant (Variation ID: 9210). For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Novel mechanisms of regulation of the expression and transcriptional activity of hepatocyte nuclear factor 4α.	Guo S	Journal of cellular biochemistry	2019	PMID: 30191603
Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes.	Flannick J	Nature genetics	2013	PMID: 24097065
Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia.	Colclough K	Human mutation	2013	PMID: 23348805
Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.	Snider KE	The Journal of clinical endocrinology and metabolism	2013	PMID: 23275527
Diazoxide-responsive hyperinsulinemic hypoglycemia caused by HNF4A gene mutations.	Flanagan SE	European journal of endocrinology	2010	PMID: 20164212
Phosphorylation of a conserved serine in the deoxyribonucleic acid binding domain of nuclear receptors alters intracellular localization.	Sun K	Molecular endocrinology (Baltimore, Md.)	2007	PMID: 17389749
Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young.	Fajans SS	The New England journal of medicine	2001	PMID: 11575290
Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels.	Shih DQ	Diabetes	2000	PMID: 10905494
Naturally occurring mutations in the human HNF4alpha gene impair the function of the transcription factor to a varying degree.	Lausen J	Nucleic acids research	2000	PMID: 10606640
The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism.	Stoffel M	Proceedings of the National Academy of Sciences of the United States of America	1997	PMID: 9371825
Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1).	Yamagata K	Nature	1996	PMID: 8945471
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c3388a6a-bb70-404d-9071-818cc4259294	-	-	-	-
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Text-mined citations for rs137853334 ...

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 Apr 13, 2026