rs1057520504

Positions:

• chr12-120994238-G-A
• chr12-120994238-G-C
• chr12-120994238-G-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) of NM_000545.8. 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 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 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID:26853433). 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 response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>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): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16606475/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 9.50

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.788G>A	p.Arg263His	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.788G>A	p.Arg263His	missense_variant	4/10
HNF1A	NM_001406915.1	c.788G>A	p.Arg263His	missense_variant	4/9
HNF1A	XM_024449168.2	c.788G>A	p.Arg263His	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.788G>A	p.Arg263His	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461296 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726908

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2022	For these reasons, this variant has been classified as Pathogenic. 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: 379138). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 16917892, 19336507, 28395978, 30293189). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 263 of the HNF1A protein (p.Arg263His). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2022	Published functional studies demonstrate reduced transcriptional activity, reduced binding to a HNF1A binding-site, and decreased nuclear and increased cytoplasmic localization of HNF1A compared to wildtype (Balamurugan 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: 26817999, 20393147, 25525159, 26853433, 16496320, 16917892, 29927023, 23517481, 30293189, 22060211, 28012402, 18838325, 19336507, 28395978, 31166087, 12453420, 18003757) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 14, 2020	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. 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. The variant caused reduction in protein transactivation, DNA binding, and nuclear localization when expressed in HeLa cells (PMID 26853433). The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Maturity onset diabetes mellitus in young Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 09, 2021	The p.R263H pathogenic mutation (also known as c.788G>A), located in coding exon 4 of the HNF1A gene, results from a G to A substitution at nucleotide position 788. The arginine at codon 263 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in several unrelated individuals reported to have maturity-onset diabetes of the young (MODY) and has shown segregation with disease in a family (Skupien J et al. Diabetes Metab, 2008 Nov;34:524-8; Radha V et al. J Clin Endocrinol Metab. 2009 Jun;94(6):1959-65; Giuffrida FMA et al. Diabetes Res Clin Pract, 2017 Jan;123:134-142; Karaca E et al. Diabetes Metab Syndr, 2017 Nov;11 Suppl 1:S491-S496; Yorifuji T et al. Pediatr Diabetes, 2018 11;19:1164-1172). In in vitro assays, this variant has been suggested to result in reduced function (Balamurugan K et al. Clin Genet. 2016 12;90(6):486-495). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Madras Diabetes Research Foundation	-	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 14, 2022

The c.788G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 263 (p.Arg263His) of NM_000545.8. 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 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 0.957, which is greater thanthe MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 16 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 19336507, 26853433, 28012402, 29927023, 31166087, internal lab contributors). Additionally, functional studies demonstrated the p.Arg263His protein has DNA binding and nuclear localization below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 26853433). 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 response to low dose sulfonylureas) (PP4_Moderate; internal lab contributors). Finally, this variant segregated with diabetes, with 9 informative meioses in multiple families with MODY (PP1_Strong; 19336507, internal lab contributors). While two additional missense variants, c.787C>T (p.Arg263His) and c.788G>T (p.Arg263Leu) have been classified as pathogenic by the ClinGen MDEP, p.Arg263His has the lowest Grantham distance and was used as the base variant to apply PM5 to Arg263Cys and PM5_Strong to Arg263Leu and thus PM5 is not applied to p.Arg263His. In summary, c.788G>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): PM1, PM2_Supporting, PP3, PS4, PS3_Supporting, PP4_Moderate, PP1_Strong. -

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

Pathogenic, no assertion criteria provided

research

Genomics And Bioinformatics Analysis Resource, Columbia University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	34
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-4.1	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.96
MutPred		0.86		Loss of MoRF binding (P = 0.0061);Loss of MoRF binding (P = 0.0061);Loss of MoRF binding (P = 0.0061);Loss of MoRF binding (P = 0.0061);
MVP		1.0
MPC		2.4
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.94

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: rs1057520504; hg19: chr12-121432041; COSMIC: COSV57459250; COSMIC: COSV57459250;