rs893256143

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP1_StrongPS3_SupportingPP4_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.599G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 200 (p.(Arg200Gln)) of transcript, e.g. NM_000545.8. This variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.926, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:23517481; internal lab contributors). Functional studies demonstrated the p.Arg200Gln protein has transactivation 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID:15522234). Lastly, this variant was identified in at least three individuals from one family with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.599G>A 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 9/30/2021): PP1_Strong, PP3, PM2_Supporting, PS3_Supporting, PS4, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16606474/MONDO:0015967/017

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HNF1A
NM_000545.8 missense

Scores

11

6

1

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 9.42

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 13 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.

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/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8 linkuse as main transcript	c.599G>A	p.Arg200Gln	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2 linkuse as main transcript	c.599G>A	p.Arg200Gln	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1 linkuse as main transcript	c.599G>A	p.Arg200Gln	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2 linkuse as main transcript	c.599G>A	p.Arg200Gln	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11 linkuse as main transcript	c.599G>A	p.Arg200Gln	missense_variant	3/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

1

AN:

152152

Hom.:

0

Cov.:

32

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

1

AN:

251336

Hom.:

0

AF XY:

0.00

AC XY:

0

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

3

AN:

1461886

Hom.:

0

Cov.:

34

AF XY:

0.00000138

AC XY:

1

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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

AF:

0.00000657

AC:

1

AN:

152152

Hom.:

0

Cov.:

32

AF XY:

0.0000135

AC XY:

1

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 12, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 200 of the HNF1A protein (p.Arg200Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg200 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been observed in individuals with HNF1A-related conditions (PMID: 9754819, 12627330), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects HNF1A function (PMID: 15522234, 16274290). 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) has been performed at Invitae 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. ClinVar contains an entry for this variant (Variation ID: 381588). This missense change has been observed in individuals with clinical features of maturity onset diabetes of the young (PMID: 12488961, 15841481, 25935773, 30663027, 33538814; Invitae). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9472859, 24069322, 30663027, 23517481, 12453420, 21224407, 18003757, 11058894, 26059258, 26479152, 32741144, 15841481, 35112188, 34789499, 36257325, 22808921, 33538814, 15522234) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. 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. Studies show this variant causes decreased transcriptional activity and abnormal localization within the cell (PMID: 15522234, 12453420). The variant is located in a region that is considered important for protein function and/or structure. -

Maturity onset diabetes mellitus in young

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 2020	The p.R200Q variant (also known as c.599G>A), located in coding exon 3 of the HNF1A gene, results from a G to A substitution at nucleotide position 599. The arginine at codon 200 is replaced by glutamine, an amino acid with highly similar properties. This variant has been identified in several individuals with maturity-onset diabetes of the young phenotype (Toaima D et al. Hum. Mutat., 2005 May;25:503-4; Chambers C et al. Pediatr Diabetes, 2016 08;17:360-7; Tatsi EB et al. Pediatr Diabetes, 2020 02;21:28-39). It was detected in a pregnant woman with gestational diabetes and a family history of diabetes (Zubkova N et al. Acta Diabetol, 2019 Apr;56:413-420). Localization studies of protein with this variant in HeLa cells demonstrated fewer cells with nuclear localization only compared to wild type (Bjørkhaug L et al. DNA Cell Biol., 2005 Nov;24:661-9). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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 rs893256143 with MODY3. -

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	Jul 17, 2023	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 maturity-onset diabetes of the young type III (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 arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2 & v3) <0.001 for a dominant condition (2 heterozygotes, 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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. p.(Arg200Trp) has been classified as pathogenic by an expert panel in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel in ClinVar. (SP) 1208 - This variant has been shown to be maternally inherited.(I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Inherited Metabolic Diseases, Karolinska University Hospital	Dec 07, 2022	- -

Diabetes mellitus

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre

-

PS1 PM2 PM5 PP3 PP5 -

Monogenic diabetes

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 10, 2022

The c.599G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to glutamine at codon 200 (p.(Arg200Gln)) of transcript, e.g. NM_000545.8. This variant segregated with diabetes, with 11 informative meioses in six families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.926, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in nine unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 23517481; internal lab contributors). Functional studies demonstrated the p.Arg200Gln protein has transactivation 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting, PMID: 15522234). Lastly, this variant was identified in at least three individuals from one family with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.599G>A 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 9/30/2021): PP1_Strong, PP3, PM2_Supporting, PS3_Supporting, PS4, PP4_Moderate. -

HNF1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 26, 2024

The HNF1A c.599G>A variant is predicted to result in the amino acid substitution p.Arg200Gln. This variant has been reported in multiple individuals with maturity-onset diabetes of the young (see for example, Figure 2, Awa et al. 2011. PubMed ID: 21224407; Table 1, Bacon et al. 2015. PubMed ID: 26479152; Table 1, Chambers et al. 2015. PubMed ID: 26059258; Table 1, Liang et al. 2020. PubMed ID: 32741144). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. In vitro experimental studies suggest this variant affects protein localization and results in reduced transactivation activity (Table 2, Chi et al. 2002. PubMed ID: 12453420; Figure 2, Gu et al. 2004. PubMed ID: 15522234; Table 1, Bjørkhaug et al. 2005. PubMed ID: 16274290). Alternate nucleotide substitutions affecting the same amino acid (p.Arg200Gly and p.Arg200Trp) have been reported in individuals with maturity-onset diabetes of the young (Table 1, Pruhova et al. 2003. PubMed ID: 12627330; Table 2, Chèvre et al. 1998. PubMed ID: 9754819). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.49

D

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

34

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

.;T;D;T;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Pathogenic

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.77

D

MetaRNN

Pathogenic

0.93

D;D;D;D;D

MetaSVM

Pathogenic

1.1

D

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Pathogenic

0.86

D

PROVEAN

Uncertain

-3.3

D;.;.;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.0010

D;.;.;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

0.99

.;.;.;.;D

Vest4

0.92

MutPred

0.76

Gain of ubiquitination at K197 (P = 0.0339);Gain of ubiquitination at K197 (P = 0.0339);Gain of ubiquitination at K197 (P = 0.0339);Gain of ubiquitination at K197 (P = 0.0339);Gain of ubiquitination at K197 (P = 0.0339);

MVP

1.0

MPC

1.7

ClinPred

0.99

D

GERP RS

4.5

gMVP

0.96

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: rs893256143; hg19: chr12-121431395; COSMIC: COSV57459659; COSMIC: COSV57459659;