rs762703502

Variant summary

Our verdict is Likely pathogenic. The variant received 10 ACMG points: 10P and 0B. PP4_ModeratePVS1

This summary comes from the ClinGen Evidence Repository: The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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 also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant failed QC in gnomAD and the frequency data is considered unreliable, therefore PM2_Supporting will not be applied. While this variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting (PMID:26287533, internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PP4_Moderate LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831842/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

HNF1A
NM_000545.8 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic reviewed by expert panel P:11

Conservation

PhyloP100: 1.68

Publications

39 publications found
Variant links:
Genes affected
HNF1A (HGNC:11621): (HNF1 homeobox A) The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5'-GTTAATNATTAAC-3'. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2015]
HNF1A Gene-Disease associations (from GenCC):
  • monogenic diabetes
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • type 1 diabetes mellitus 20
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
  • diabetes mellitus, noninsulin-dependent
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • maturity-onset diabetes of the young type 3
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
  • hyperinsulinism due to HNF1A deficiency
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • maturity-onset diabetes of the young
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • nonpapillary renal cell carcinoma
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 10 ACMG points.

PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HNF1ANM_000545.8 linkc.864delG p.Pro291GlnfsTer51 frameshift_variant Exon 4 of 10 ENST00000257555.11 NP_000536.6 P20823E0YMI7
HNF1ANM_001306179.2 linkc.864delG p.Pro291GlnfsTer51 frameshift_variant Exon 4 of 10 NP_001293108.2 P20823E0YMI7
HNF1ANM_001406915.1 linkc.864delG p.Pro291GlnfsTer51 frameshift_variant Exon 4 of 9 NP_001393844.1
HNF1AXM_024449168.2 linkc.864delG p.Pro291GlnfsTer51 frameshift_variant Exon 4 of 9 XP_024304936.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HNF1AENST00000257555.11 linkc.864delG p.Pro291GlnfsTer51 frameshift_variant Exon 4 of 10 1 NM_000545.8 ENSP00000257555.5 A0A0A0MQU7

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152210
Hom.:
0
Cov.:
32
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000964
AC:
23
AN:
238620
AF XY:
0.0000926
show subpopulations
Gnomad AFR exome
AF:
0.0000684
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000983
Gnomad NFE exome
AF:
0.000168
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000961
AC:
14
AN:
1457192
Hom.:
0
Cov.:
33
AF XY:
0.0000152
AC XY:
11
AN XY:
724646
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33418
American (AMR)
AF:
0.0000228
AC:
1
AN:
43806
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25920
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39640
South Asian (SAS)
AF:
0.0000233
AC:
2
AN:
85736
European-Finnish (FIN)
AF:
0.0000189
AC:
1
AN:
52938
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5762
European-Non Finnish (NFE)
AF:
0.00000811
AC:
9
AN:
1109778
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60194
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.311
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
152210
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
African (AFR)
AF:
0.00
AC:
0
AN:
41452
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68030
Other (OTH)
AF:
0.00
AC:
0
AN:
2092

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:11
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Apr 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Pro291Glnfs*51) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 26287533). ClinVar contains an entry for this variant (Variation ID: 435424). For these reasons, this variant has been classified as Pathogenic. -

Aug 06, 2020
Athena Diagnostics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. -

Dec 23, 2016
Eurofins Ntd Llc (ga)
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 03, 2023
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9313763, 17054605, 30476138, 26287533, 33535453, 34587721, 35112188, 25414397) -

Maturity onset diabetes mellitus in young Pathogenic:3
Mar 30, 2025
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.864delG pathogenic mutation, located in coding exon 4 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 864, causing a translational frameshift with a predicted alternate stop codon (p.P291Qfs*51). This variant was reported in individual(s) with features consistent with HNF1A-related maturity-onset diabetes of the young (Ludovico O et al. PLoS ONE, 2015 Aug;10:e0135855). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

-
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. Sufficient evidence is found to confer the association of this particular variant rs762703502 with MODY3. -

Nov 06, 2020
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Pro291GlnfsX51 variant in HNF1A has been reported in 2 individuals with monogenic diabetes (Delvecchio 2014 PMID: 25414397, Ludovico 2015 PMID: 26287533) and has also been reported in ClinVar (Variation ID: 435424). It has been identified in 0.01% (2/13784) of African chromosomes and 0.01% (8/101808) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 291 and leads to a premature termination codon 51 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the HNF1A gene is an established disease mechanism in autosomal dominant maturity onset diabetes of the young (MODY). In summary although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PVS1, PS4_Supporting. Please note, this site fails multiple random filters in exomes in gnomAD and is at a multiallelic site; therefore, follow-up Sanger analysis is recommended for exome data. -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1
Mar 11, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Monogenic diabetes Pathogenic:1
Jun 09, 2025
ClinGen Monogenic Diabetes Variant Curation Expert Panel
Significance:Likely pathogenic
Review Status:reviewed by expert panel
Collection Method:curation

The c.864del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 291 (NM_000545.8), adding 51 novel amino acids before encountering a stop codon (p.Pro291GlnfsTer51). This variant, located in biologically-relevant exon 4 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 also identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and responded to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). This variant failed QC in gnomAD and the frequency data is considered unreliable, therefore PM2_Supporting will not be applied. While this variant was identified in at least 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting (PMID: 26287533, internal lab contributors). In summary, c.864del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/23): PVS1, PP4_Moderate -

Maturity-onset diabetes of the young type 3 Pathogenic:1
Apr 08, 2016
Genetic Services Laboratory, University of Chicago
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

HNF1A-related disorder Pathogenic:1
Jun 04, 2024
PreventionGenetics, part of Exact Sciences
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

The HNF1A c.864delG variant is predicted to result in a frameshift and premature protein termination (p.Pro291Glnfs*51). This variant has been reported in individuals with diabetes mellitus or Maturity-Onset Diabetes of the Young (MODY) (e.g., Wheeler et al. 2013. PubMed ID: 24355479; Ludovico et al. 2015. PubMed ID: 26287533; Yalçıntepe et al. 2021. PubMed ID: 33565752). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic or likely pathogenic by multiple submitters to ClinVar, including the ClinGen Monogenic Diabetes Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/435424). Frameshift and other loss-of-function variants in HNF1A are expected to be pathogenic. Based on the collective evidence, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.7
Mutation Taster
=0/200
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

Publications

Other links and lift over

dbSNP: rs762703502; hg19: chr12-121432114; COSMIC: COSV57458899; COSMIC: COSV57458899; API