chr12-120994237-C-T

Position:

• chr12-120994237-C-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PP1_Strong PS3_Supporting PP4_Moderate PP3 PM2_Supporting PM1 PM5 PS4

This summary comes from the ClinGen Evidence Repository: The c.787C>T variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 263 (p.Arg263Cys) 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 in the gnomAD v2.1.1 European non-Finnish population, and there is one copy 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 30155490, 12574234, 25414397, 9287053; internal lab contributors). Additionally, another missense variant, c.788G>A (p.Arg263His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg263Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg263Cys protein has DNA binding and transactivation activity below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID:12574234). Also, 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). Lastly, this variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID:12574234, internal lab contributors). In summary, c.787C>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 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PM5, PS3_Supporting, PP4_Moderate, PP1_Strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831834/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 2.43

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 17 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.
• PM5: 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.787C>T	p.Arg263Cys	missense_variant	4/10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.787C>T	p.Arg263Cys	missense_variant	4/10		NP_001293108.2
HNF1A	NM_001406915.1	c.787C>T	p.Arg263Cys	missense_variant	4/9		NP_001393844.1
HNF1A	XM_024449168.2	c.787C>T	p.Arg263Cys	missense_variant	4/9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.787C>T	p.Arg263Cys	missense_variant	4/10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249174 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000999

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: 6.84e-7 AC: 1 AN: 1461168 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

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

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 06, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 263 of the HNF1A protein (p.Arg263Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with maturity-onset diabetes of the young (MODY) (PMID: 12574234, 25414397, 30586318). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 562367). 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: 12574234, 27899486). This variant disrupts the p.Arg263 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19336507, 30293189). 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, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 14, 2022

The c.787C>T variant in the HNF1 homeobox A] gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 263 (p.Arg263Cys) 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 in the gnomAD v2.1.1 European non-Finnish population, and there is one copy in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 21 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 30155490, 12574234, 25414397, 9287053; internal lab contributors). Additionally, another missense variant, c.788G>A (p.Arg263His), has been interpreted as pathogenic by the ClinGen MDEP and p.Arg263Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg263Cys protein has DNA binding and transactivation activity below 40% of wild type, indicating that this variant impacts protein function (PS3_Supporting; PMID: 12574234). Also, 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). Lastly, this variant segregated with diabetes, with 7 informative meioses in 2 families with MODY (PP1_Strong; PMID: 12574234, internal lab contributors). In summary, c.787C>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 9/30/2021): PM1, PM2_Supporting, PP3, PS4, PM5, PS3_Supporting, PP4_Moderate, PP1_Strong. -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2024

The p.R263C pathogenic mutation (also known as c.787C>T), located in coding exon 4 of the HNF1A gene, results from a C to T substitution at nucleotide position 787. The arginine at codon 263 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in one or more individuals with features consistent with maturity-onset diabetes of the young (MODY) and segregated with disease in at least one family (Iwasaki N et al. Diabetes, 1997 Sep;46:1504-8; Bjørkhaug L et al. J Clin Endocrinol Metab, 2003 Feb;88:920-31; Delvecchio M et al. Diabetes Care, 2014 Dec;37:e258-60; Mirshahi UL et al. Am J Hum Genet, 2022 Nov;109:2018-2028). In multiple assays testing HNF1A function, this variant showed functionally abnormal results (Yang Q et al. Biochem Biophys Res Commun, 1999 Dec;266:196-202; Bjørkhaug L et al. J Clin Endocrinol Metab, 2003 Feb;88:920-31). Another variant at the same codon, p.R263H (c.788G>A) has also been reported in association with MODY (Skupien J et al. Diabetes Metab, 2008 Nov;34:524-8). 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 supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	.;D;D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.99	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.1	D;.;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.98
MutPred		0.87		Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);Loss of MoRF binding (P = 9e-04);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		4.8
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

Other links and lift over

dbSNP: rs771108132; hg19: chr12-121432040; COSMIC: COSV57460808; COSMIC: COSV57460808;