chr12-120988898-G-A

Variant names:

• chr12-120988898-G-A
• rs753998395
• NM_000545.8:c.392G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PP1_Strong PS4 PS2 PS3_Supporting PP4_Moderate PM2_Supporting PP3 PM1

This summary comes from the ClinGen Evidence Repository: The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID:32910913 and PMID:10585442) (PS3_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831746/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.51
• Publications: 28 publications found

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)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000545.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	NM_000545.8	MANE Select	c.392G>A	p.Arg131Gln	missense	Exon 2 of 10	NP_000536.6
	HNF1A	NM_001306179.2		c.392G>A	p.Arg131Gln	missense	Exon 2 of 10	NP_001293108.2
	HNF1A	NM_001406915.1		c.392G>A	p.Arg131Gln	missense	Exon 2 of 9	NP_001393844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HNF1A	ENST00000257555.11	TSL:1 MANE Select	c.392G>A	p.Arg131Gln	missense	Exon 2 of 10	ENSP00000257555.5
	HNF1A	ENST00000544413.2	TSL:1	c.392G>A	p.Arg131Gln	missense	Exon 2 of 10	ENSP00000438804.1
	HNF1A	ENST00000538646.5	TSL:1	n.392G>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000443964.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251390 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461890 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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: 53418

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

Alfa AF: 0.000145 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Oct 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate decreased target promoter activity compared to wildtype (PMID: 23607861); 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; This variant is associated with the following publications: (PMID: 24097065, 29927023, 28012402, 21761282, 34462253, 30586318, 25414397, 8945470, 27899486, 28410371, 11058894, 12442280, 18838325, 18513302, 27634015, 19754856, 30754156, 12453420, 17937063, 30754209, 23607861, 22060211, 34108472, 18003757, 36227502, 24323243)

Sep 16, 2018

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Oct 15, 2021

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple individuals with clinical features associated with this gene, including multiple de novo occurrences. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant shows reduced transcriptional activity compared to wildtype in multiple cell lines (PMID: 23607861, 27899486, 32910913). The variant is located in a region that is considered important for protein function and/or structure.

Jan 15, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 131 of the HNF1A protein (p.Arg131Gln). This variant is present in population databases (rs753998395, gnomAD 0.0009%). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 8945470). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562373). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HNF1A protein function. Experimental studies have shown that this missense change affects HNF1A function (PMID: 27899486). For these reasons, this variant has been classified as Pathogenic.

Maturity-onset diabetes of the young type 3 Pathogenic:2

Genomics And Bioinformatics Analysis Resource, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The p.Arg131Gln variant in HNF1A has been reported in at least 15 individuals with maturity-onset diabetes of the young, segregated with disease in 4 affected relatives from 2 families (PMID: 24323243, 12442280, 22060211, 17937063, 18838325, 11315851, 9032114, 9287053, 18003757), but has been identified in 0.0009% (1/113698) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753998395). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic by Columbia University in ClinVar (Variation ID: 562373). In vitro functional studies provide some evidence that the p.Arg131Gln variant may slightly impact protein function (PMID: 27899486). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Arg131Gln variant is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 28410371). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on more affected individuals with the variant than expected, low frequency in the general population, location in a functional domain, and in vitro functional studies. ACMG/AMP Criteria applied: PS4, PM2, PM1, PP3, PP1, PS3_Supporting (Richards 2015).

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

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Monogenic diabetes Pathogenic:1

Aug 11, 2021

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.392G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 131 (p.(R131Q)) of NM_000545.8. This variant has a minor allele frequency of 0.000008795 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (≤0.00002 and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, which is greater than the MDEP threshold of 0.70 (PP3), which is supported by functional studies that demonstrated the p.Arg131Gln protein has abnormal nuclear localization and transactivation below 40% of wildtype (PMID: 32910913 and PMID: 10585442) (PS3_Supporting). This variant resides in an amino acid within the HNF1α DNA binding domain that directly binds DNA, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in at least 40 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:9287053, PMID:10447526, PMID:894547, PMID:9032114, PMID:1115175, PMID:11315851, PMID:12442290, PMID:162495, PMID:19754856, PMID:2095039, ClinVar ID: 562373, internal lab contributors). This variant segregated with diabetes, with at least 20 informative meioses in 6 families with MODY (PP1_Strong; PMID:10447526, PMID:894547, PMID:9032114, PMID:11315851, internal lab contributors). This variant was identified as a de novo occurrence with confirmed parental relationships in 2 individuals with diabetes, but whose clinical picture is not highly specific for HNF1A-MODY (MODY probability calculator results <50%)(PS2; PMID:24323243). Additionally, at least 2 individuals have a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and sulfonylurea sensitive) (PP4_Moderate; internal lab contributors). Taken together, this evidence supports the classification of this variant as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP1_Strong, PS2, PS4, PP4_Moderate, PM1, PP3, PM2_Supporting, PS3_Supporting.

Maturity onset diabetes mellitus in young Pathogenic:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: 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 rs753998395 with MODY3.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.92		Loss of MoRF binding (P = 0.0666)
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.90
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs753998395; hg19: chr12-121426701; COSMIC: COSV57462220;