12-120993601-G-A

Position:

• chr12-120993601-G-A

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS4 PM1 PP1_Strong PS3_Supporting PP4_Moderate PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.608G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 203 (p.(Arg203His)) of NM_000545.8. This variant segregated with diabetes, in more than 10 families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in at least 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23348805, 27913849, internal lab contributors). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg203His protein has abnormal nuclear localization below 40% of wildtype, indicating that this variant impacts protein function (PMID:32910913) (PS3_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID:27913849). In summary, c.608G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS4, PP1_Strong, PM1, PM2_Supporting, PP4_Moderate,PP3, PS3_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA153100/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 9.42

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]

ACMG classification

Verdict is Pathogenic. Variant got 15 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/exons	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.608G>A	p.Arg203His	missense_variant	3/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.608G>A	p.Arg203His	missense_variant	3/10		NP_001293108.2
HNF1A	NM_001406915.1	c.608G>A	p.Arg203His	missense_variant	3/9		NP_001393844.1
HNF1A	XM_024449168.2	c.608G>A	p.Arg203His	missense_variant	3/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.608G>A	p.Arg203His	missense_variant	3/10	1	NM_000545.8	ENSP00000257555	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251318 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135870

Gnomad AFR exome AF: 0.0000616

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: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 203 of the HNF1A protein (p.Arg203His). This variant is present in population databases (rs587780357, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of maturity-onset diabetes of the young (PMID: 10588527, 12627330, 15928245, 30293189). ClinVar contains an entry for this variant (Variation ID: 129235). 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. Experimental studies have shown that this missense change affects HNF1A function (PMID: 16274290). This variant disrupts the p.Arg203 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21168233, 30293189, 31363388; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2024	A different missense change at this residue (p.(R203C)) has been reported as pathogenic in the published literature and at GeneDx in association with MODY (PMID: 31363388, 21168233); 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; Classified as pathogenic by the ClinGen Monogenic Diabetes Expert Panel (ClinVar SCV002499516.1); This variant is associated with the following publications: (PMID: 18003757, 12488961, 15657605, 11772903, 23274891, 16274290, 15928245, 27271189, 23348805, 12453420, 10588527, 12627330, 30293189, 35472491, 34789499, 36836406, 36227502, 33046911, 32910913, 33950347, 35673428, 36257325, 33477506, 35921062, 27913849, 31363388, 21168233) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 18, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with MODY. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Assessment of experimental evidence suggests this variant results in abnormal protein function. 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

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 rs587780357 with MODY3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2021	The p.R203H variant (also known as c.608G>A), located in coding exon 3 of the HNF1A gene, results from a G to A substitution at nucleotide position 608. The arginine at codon 203 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in multiple individuals and families with features of maturity-onset diabetes of the young (Thanabalasingham G et al. Diabetes, 2013 Apr;62:1329-37; Shepherd M et al. Diabetes Care, 2016 Nov;39:1879-1888; Bansal V et al. BMC Med, 2017 12;15:213; Johansson BB et al. Diabetologia, 2017 04;60:625-635; Bonnefond A et al. Nat Metab, 2020 10;2:1126-1134; Ivanoshchuk DE et al. J Pers Med, 2021 Jan;11:). Based on internal structural analysis, this variant is mildly destabilizing to the local structure (Chi YI et al. Mol Cell, 2002 Nov;10:1129-37; P S et al. PLoS One, 2017 Apr;12:e0174953). This amino acid position is highly conserved in available vertebrate species. 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. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 10, 2022

The c.608G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 203 (p.(Arg203His)) of NM_000545.8. This variant segregated with diabetes, in more than 10 families with MODY (PP1_Strong; internal lab contributors). Additionally, this variant was identified in at least 15 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 23348805, 27913849, internal lab contributors). 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.958, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg203His protein has abnormal nuclear localization below 40% of wildtype, indicating that this variant impacts protein function (PMID: 32910913) (PS3_Supporting). Lastly, this variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative) (PP4_Moderate; PMID:27913849). In summary, c.608G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 9/30/21): PS4, PP1_Strong, PM1, PM2_Supporting, PP4_Moderate,PP3, PS3_Supporting. -

Diabetes mellitus type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 23, 2017

DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.608G>A, in exon 3 that results in an amino acid change, p.Arg203His. The p.Arg203His change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Arg203His substitution appears to be possibly damaging using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). The p.Arg203His amino acid change has been described in the literature in one patient with early-onset diabetes (Ng et al., 1999. Diabet Med 16:956-63). In addition, different pathogenic sequence changes affecting the same amino acid residue (p.Arg203) has been described in patients with HNF1A-related maturity-onset diabetes of the young (MODY) (Lopez et al., 2011. Diabetes Res Clin Pract 91:208-12; Colclough et al., 2013. Hum Mutat 34:669-85; Yamada et al., 1999. Diabetes 48: 645-8). -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Geisinger Clinic, Geisinger Health System

Aug 02, 2022

PS4, PP1_Strong, PM1, PM2, PP4_Moderate, PP3, PS3_Supporting -

HNF1A-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 29, 2024

The HNF1A c.608G>A variant is predicted to result in the amino acid substitution p.Arg203His. This variant has been reported in several individuals with maturity-onset diabetes of the young (MODY) (see examples: Ng et al. 1999. PubMed ID: 10588527; Wang et al. 2018. PubMed ID: 30293189; Ma et al. 2020. PubMed ID: 32238361; Thanabalasingham et al. 2012. PubMed ID: 23274891; Wang DW et al 2022. PubMed ID: 35921062). In vitro functional studies demonstrate that expression of this variant results in protein mislocalization and reduced DNA binding ability compared to wild-type (Bjørkhaug L et al 2005. PubMed ID: 16274290; Figure S5, Althari et al. 2020. PubMed ID: 32910913). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant has been interpreted as pathogenic by the ClinGen monogenic diabetes variant curation expert panel (VCEP, https://www.ncbi.nlm.nih.gov/clinvar/variation/129235/). Additionally, different missense changes impacting the same amino acid (p.Arg203Ser, p.Arg203Gly, p.Arg203Cys) have been reported in individuals with MODY (Colclough et al. 2013. PubMed ID: 23348805; Lopez et al. 2011. PubMed ID: 21168233). Taken together, the c.608G>A (p.Arg205His) variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;D;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.9	D;.;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;.;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	.;.;.;.;D
Vest4		0.96
MutPred		0.88		Gain of ubiquitination at K198 (P = 0.0371);Gain of ubiquitination at K198 (P = 0.0371);Gain of ubiquitination at K198 (P = 0.0371);Gain of ubiquitination at K198 (P = 0.0371);Gain of ubiquitination at K198 (P = 0.0371);
MVP		0.99
MPC		2.2
ClinPred		0.99	D
GERP RS		4.5
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

Other links and lift over

dbSNP: rs587780357; hg19: chr12-121431404;