VCV002505495.3 - ClinVar

NM_175914.5(HNF4A):c.337G>T (p.Asp113Tyr)

Germline

Top reviewed classifications are shown here.

Submission summary:

1 submission

1 submitter

1 condition

Reviewed by expert panel

Uncertain significance

Feb 2024 by ClinGen Monoge… FDA Recognized Database

for Monogenic diabetes

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_175914.5(HNF4A):c.337G>T (p.Asp113Tyr)

Variation ID: 2505495 Accession: VCV002505495.3

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20q13.12 20: 44413711 (GRCh38) [ NCBI UCSC ] 20: 43042351 (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	Jun 17, 2023	Mar 10, 2024	Feb 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_175914.5:c.337G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_787110.2:p.Asp113Tyr	missense
NM_000457.6:c.403G>T	NP_000448.3:p.Asp135Tyr	missense
NM_001030003.3:c.337G>T	NP_001025174.1:p.Asp113Tyr	missense
NM_001030004.3:c.337G>T	NP_001025175.1:p.Asp113Tyr	missense
NM_001258355.2:c.382G>T	NP_001245284.1:p.Asp128Tyr	missense
NM_001287182.2:c.328G>T	NP_001274111.1:p.Asp110Tyr	missense
NM_001287183.2:c.328G>T	NP_001274112.1:p.Asp110Tyr	missense
NM_001287184.2:c.328G>T	NP_001274113.1:p.Asp110Tyr	missense
NM_178849.3:c.403G>T	NP_849180.1:p.Asp135Tyr	missense
NM_178850.3:c.403G>T	NP_849181.1:p.Asp135Tyr	missense
NC_000020.11:g.44413711G>T
NC_000020.10:g.43042351G>T
NG_009818.1:g.62911G>T
LRG_483:g.62911G>T
LRG_483t1:c.337G>T	LRG_483p1:p.Asp113Tyr
LRG_483t2:c.403G>T	LRG_483p2:p.Asp135Tyr
LRG_483t3:c.328G>T	LRG_483p3:p.Asp110Tyr

... more HGVS ... less HGVS

Protein change

D110Y, D113Y, D128Y, D135Y

Other names

NM_175914.5:c.337G>T

Canonical SPDI

NC_000020.11:44413710:G:T

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.

Links

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		-	-	GRCh38 GRCh37	588	601

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.
Monogenic diabetes	Uncertain significance (1)	reviewed by expert panel	Feb 25, 2024	RCV003234762.3

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.
Uncertain significance (Feb 25, 2024)	reviewed by expert panel (ClinGen Diabetes ACMG Specifications HNF4A V2.0.0) Method: curation	Monogenic diabetes (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Monogenic Diabetes Variant Curation Expert Panel FDA Recognized Database Accession: SCV003932668.3 First in ClinVar: Jun 17, 2023 Last updated: Mar 10, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/eb06cffd-4920-4549-b807-cf7d878b92e5 Comment: The c.337G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 113 (p.(Asp113Tyr)) … (more) The c.337G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 113 (p.(Asp113Tyr)) of NM_175914.5. This variant resides in an amino acid within the HNF-4alpha DNA binding domain that directly binds DNA and is necessary for homodimer formation, which is defined as critical for the protein's function by the ClinGen MDEP (PM1; PMID: 18829458). Functional studies demonstrated the p.Asp113Tyr protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_supporting; PMID: 12110948). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, HNF1A was not tested, and the individual had positive anti-GAD antibodies; thus, PP4 criteria was not applied (PMID: 11232004). In summary, c.337G>T meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PS3_suppporting, PM1, PM2_supporting, PP3. (less)

Comment:

The c.337G>T variant in the hepatocyte nuclear factor-4 alpha gene, HNF4A, causes an amino acid change of aspartic acid to tyrosine at codon 113 (p.(Asp113Tyr)) of NM_175914.5. This variant resides in an amino acid within the HNF-4alpha DNA binding domain that directly binds DNA and is necessary for homodimer formation, which is defined as critical for the protein's function by the ClinGen MDEP (PM1; PMID: 18829458). Functional studies demonstrated the p.Asp113Tyr protein has DNA binding below 60% of wild type, indicating that this variant impacts protein function (PS3_supporting; PMID: 12110948). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.955, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in an individual with diabetes; however, the calculated MODY probability is <50%, HNF1A was not tested, and the individual had positive anti-GAD antibodies; thus, PP4 criteria was not applied (PMID: 11232004). In summary, c.337G>T meets the criteria to be classified as a VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0.0, approved 11/16/2022): PS3_suppporting, PM1, PM2_supporting, PP3.

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/eb06cffd-4920-4549-b807-cf7d878b92e5	-	-	-	-

Text-mined citations for this variant ...

Record last updated Mar 11, 2024

ClinVar Genomic variation as it relates to human health

NM_175914.5(HNF4A):c.337G>T (p.Asp113Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...