rs137853243

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PP4_ModeratePP3PM2_SupportingPS3PS4_ModeratePP1_StrongPM1

This summary comes from the ClinGen Evidence Repository: The c.335C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 112 (p.(Pro112Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro112Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMID:32910913). Lastly, this variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). In summary, c.335C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PM1_Supporting, PM2_Supporting, PP4_Moderate, PS4_Moderate,PS3_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA124475/MONDO:0015967/017

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

14

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 7.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 2 of 10	ENST00000257555.11	NP_000536.6	P20823E0YMI7
HNF1A	NM_001306179.2 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 2 of 10		NP_001293108.2	P20823E0YMI7
HNF1A	NM_001406915.1 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 2 of 9		NP_001393844.1
HNF1A	XM_024449168.2 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 2 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 link	c.335C>T	p.Pro112Leu	missense_variant	Exon 2 of 10	1	NM_000545.8	ENSP00000257555.5		A0A0A0MQU7

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251202

Hom.:

0

AF XY:

0.00000736

AC XY:

1

AN XY:

135780

show subpopulations

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 SAS 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:

1461866

Hom.:

0

Cov.:

33

AF XY:

0.00000275

AC XY:

2

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2022	Published functional studies demonstrate impaired DNA binding and significantly reduced transcriptional activity (Bjrkhaug et al., 2000; Xu et al., 2002; Najmi et al., 2016); 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: 17989309, 12107757, 12574234, 15657605, 27899486, 26431509, 24915262, 18003757, 12453420, 11162430, 21518407, 32910913) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 13, 2023	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 112 of the HNF1A protein (p.Pro112Leu). This variant is present in population databases (rs137853243, gnomAD 0.0009%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (MODY) (PMID: 11162430, 21518407). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 14942). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1A protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HNF1A function (PMID: 11162430, 27899486, 35472491). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2016	- -

Maturity-onset diabetes of the young type 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with type III maturity-onset diabetes of the young (MODY type III; MIM#600496). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated DNA-binding domain (PMID: 32910913). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple families with MODY (ClinVar, PMIDs: 11162430, 12107757, 21518407, 32238361). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies performed by multiple laboratories have shown that it reduced protein expression, transcriptional activity, DNA binding and also resulted in impaired subcellular localisation (PMID: 32910913). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2003	- -

Maturity onset diabetes mellitus in young

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 19, 2025

Variant summary: HNF1A c.335C>T (p.Pro112Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251342 control chromosomes. c.335C>T has been reported in the literature in multiple individuals affected with clinical features of maturity-onset diabetes of the young (MODY) (examples: Bjorkhaug_2000, Hameed_2011, Xu_2005). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11162430, 15657605, 21518407). ClinVar contains an entry for this variant (Variation ID: 14942). Based on the evidence outlined above, the variant was classified as pathogenic. -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 08, 2022

The c.335C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to leucine at codon 112 (p.(Pro112Leu)) of NM_000545.8. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.966, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). This variant was identified in two individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Pro112Leu protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate, PMID: 32910913). Lastly, this variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). In summary, c.335C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PP3, PM1_Supporting, PM2_Supporting, PP4_Moderate, PS4_Moderate,PS3_Moderate, PP1_Strong. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.50

D

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

32

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

.;D;D;D;D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.93

D

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.88

D

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

PrimateAI

Pathogenic

0.84

D

PROVEAN

Pathogenic

-7.6

D;.;.;.;D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0010

D;.;.;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;D

Vest4

0.94

MutPred

0.90

Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);Gain of MoRF binding (P = 0.0468);

MVP

0.98

MPC

2.1

ClinPred

1.0

D

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs137853243; hg19: chr12-121426644; COSMIC: COSV57465455;