chr12-120994264-C-T

Position:

• chr12-120994264-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.814C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cystine at codon 272 (p.(Arg272Cys) of transcript, e.g. 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 18003757, 28701371, 25414397, 11719843, 10447526; internal lab contributors). The variant segregated with diabetes, with at least fifteen informative meioses in at least sixteen families with MODY (PP1_Strong; internal lab contributors). Another missense variant, c. 815G>A, p.Arg272His, has been interpreted as pathogenic by the ClinGen MDEP and p.Arg272Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg272Cys protein has DNA binding below 40% of wild type and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID:10333057). Lastly, this variant was identified in at least five 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 sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.814C>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, PP1_Strong, PM5, PS3_Supporting, PP4_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA386966363/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 1.79

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 17 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.814C>T	p.Arg272Cys	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.814C>T	p.Arg272Cys	missense_variant	4/10
HNF1A	NM_001406915.1	c.814C>T	p.Arg272Cys	missense_variant	4/9
HNF1A	XM_024449168.2	c.814C>T	p.Arg272Cys	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.814C>T	p.Arg272Cys	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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	GeneDx	Sep 27, 2022	Published in vitro functional studies demonstrate a dominant negative effect resulting in no trans-activating or DNA-binding activity (Yoshiuchi et al., 1999); 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: 25414397, 10333057, 28701371, 18003757, 16562587, 16274290, 10447526, 11719843, 12453420) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 16, 2021	The HNF1A c.814C>T; p.Arg272Cys variant (rs1555212014) is reported in the literature in multiple individuals affected with maturity-onset diabetes of the young (MODY, Kagami-Takasugi 2006, Kristinsson 2001, Yoshiuchi 1999). Functional analyses of the variant protein show abolished transactivation activity and DNA binding (Yoshiuchi 1999). This variant is reported in ClinVar (Variation ID: 447503) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.815G>A, p.Arg272His; c.814C>A, p.Arg272Ser) have been reported in individuals with MODY and are considered pathogenic (Bellanne-Chantelot 2008, Yamada 1997). The arginine at codon 272 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.941). Based on available information, this variant is considered to be pathogenic. References: Bellanne-Chantelot C et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2008 Feb;57(2):503-8. PMID: 18003757. Kagami-Takasugi M et al. Molecular genetic analysis of MODY candidate genes in Japanese patients with non-obese juvenile onset diabetes mellitus. J Pediatr Endocrinol Metab. 2006 Feb;19(2):143-8. PMID: 16562587 Kristinsson SY et al. MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia. 2001 Nov;44(11):2098-103. PMID: 11719843 Yamada S et al. Identification of mutations in the hepatocyte nuclear factor (HNF)-1 alpha gene in Japanese subjects with IDDM. Diabetes. 1997 Oct;46(10):1643-7. PMID: 9313763. Yoshiuchi I et al. Three new mutations in the hepatocyte nuclear factor-1alpha gene in Japanese subjects with diabetes mellitus: clinical features and functional characterization. Diabetologia. 1999 May;42(5):621-6. PMID: 10333057 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the HNF1A protein (p.Arg272Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with maturity onset diabetes of the young (PMID: 10333057, 11719843, 16562587). ClinVar contains an entry for this variant (Variation ID: 447503). 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: 10333057). This variant disrupts the p.Arg272 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9032114, 21823540, 29439679). 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	Athena Diagnostics	Aug 29, 2022	This variant has been identified in multiple unrelated individuals with clinical features associated with this gene including a de novo case. This variant appears to segregate with disease in at least one family. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. Variant protein abolished DNA binding and transactivation activity (PMID: 10333057). 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	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. However, more evidence is required to confer the association of this particular variant rs1555212014 with MODY3. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2021	The p.R272C pathogenic mutation (also known as c.814C>T), located in coding exon 4 of the HNF1A gene, results from a C to T substitution at nucleotide position 814. The arginine at codon 272 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first reported in a Japanese patient with a clinical diagnosis of MODY; this mutation was shown to abolish transactivation activity, resulting in impaired insulin and glucagon secretion due to a dominant negative effect (Yoshiuchi I, Diabetologia 1999 May; 42(5):621-6). This mutation has since been reported in multiple MODY patients and kindreds (Lehto M, Diabetologia 1999 Sep; 42(9):1131-7; Kristinsson SY, Diabetologia 2001 Nov; 44(11):2098-103; Delvecchio M, Diabetes Care 2014 Dec; 37(12):e258-60). In addition, alterations at the same codon (p.R272H and p.R272S) have been reported in MODY families (Colclough K, Hum. Mutat. 2013 May; 34(5):669-85). Based on the supporting evidence, p.R272C is interpreted as a disease-causing mutation. -

Diabetes mellitus type 1;C0011860:Type 2 diabetes mellitus;C1838100:Maturity-onset diabetes of the young type 3;C1840646:Hepatic adenomas, familial;C2675866:Type 1 diabetes mellitus 20;CN074294:Nonpapillary renal cell carcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 06, 2022

- -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 15, 2022

The c.814C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cystine at codon 272 (p.(Arg272Cys) of transcript, e.g. 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) and is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.941, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 18003757, 28701371, 25414397, 11719843, 10447526; internal lab contributors). The variant segregated with diabetes, with at least fifteen informative meioses in at least sixteen families with MODY (PP1_Strong; internal lab contributors). Another missense variant, c. 815G>A, p.Arg272His, has been interpreted as pathogenic by the ClinGen MDEP and p.Arg272Cys has a greater Grantham distance (PM5). Functional studies demonstrated the p.Arg272Cys protein has DNA binding below 40% of wild type and transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 10333057). Lastly, this variant was identified in at least five 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 sulfonylurea) (PP4_Moderate; internal lab contributors). In summary, c.814C>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, PP1_Strong, PM5, PS3_Supporting, PP4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;D;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	D;.;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.97
MutPred		0.81		Gain of methylation at K273 (P = 0.0249);Gain of methylation at K273 (P = 0.0249);Gain of methylation at K273 (P = 0.0249);Gain of methylation at K273 (P = 0.0249);
MVP		1.0
MPC		2.5
ClinPred		0.99	D
GERP RS		3.9
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555212014; hg19: chr12-121432067; COSMIC: COSV57462785; COSMIC: COSV57462785;