rs137853238

chr12-120994265-G-Achr12-120994265-G-Cchr12-120994265-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Moderate PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000545.8(HNF1A):c.815G>A(p.Arg272His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• 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 20 ACMG points.

• PS1: Transcript NM_000545.8 (HNF1A) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000545.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-120994264-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 447503.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 12-120994265-G-A is Pathogenic according to our data. Variant chr12-120994265-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 14931.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120994265-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.815G>A	p.Arg272His	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.815G>A	p.Arg272His	missense_variant	4/10
HNF1A	NM_001406915.1	c.815G>A	p.Arg272His	missense_variant	4/9
HNF1A	XM_024449168.2	c.815G>A	p.Arg272His	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.815G>A	p.Arg272His	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:11

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2022	Published functional studies demonstrate normal expression level and mobility, but reduced DNA binding and decreased transactivation activity compared to wild-type (Vaxillaire 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: 9313763, 27077911, 21823540, 28410371, 15114102, 31483937, 9166684, 9032114, 26431509, 29439679, 29207974, 31960584, 33242514, 23610083, 12453420, 18003757, 19150152, 10333057, 11719843, 10585442) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 14, 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) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. ClinVar contains an entry for this variant (Variation ID: 14931). This missense change has been observed in individuals with maturity-onset diabetes of the young (MODY) (PMID: 9032114, 21823540, 29439679). 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 272 of the HNF1A protein (p.Arg272His). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 23, 2023	This variant has been identified in multiple unrelated individuals with MODY and segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations. (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)) At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 10585442, 37396188) The variant is located in a region that is considered important for protein function and/or structure. -

Maturity onset diabetes mellitus in young Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Madras Diabetes Research Foundation	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 09, 2019	The p.R272H pathogenic mutation (also known as c.815G>A), located in coding exon 4 of the HNF1A gene, results from a G to A substitution at nucleotide position 815. The arginine at codon 272 is replaced by histidine, an amino acid with highly similar properties. This variant has been described in multiple patients and families with a MODY diagnosis (Klupa T et al. Diabetes Care, 2002 Dec;25:2292-301; Pruhova S et al. Diabetologia, 2003 Feb;46:291-5; McDonald TJ et al. Diabet. Med., 2011 Sep;28:1028-33) and has segregated with disease in multiple families (Rozenkova K et al. J. Clin. Endocrinol. Metab., 2015 Dec;100:E1540-9; Dusátková P et al. J. Pediatr. Endocrinol. Metab., 2011;24:377-9; Glucksmann MA et al. Diabetes, 1997 Jun;46:1081-6). One report included an individual heterozygous for this alteration who developed diabetic ketoacidosis due to poor control and dehydration. (Pruhova S et al. Diabetes Care, 2013 Sep;36:2573-4). In addition, alterations at the same codon (p.R272C and p.R272S) have been reported in MODY families (Colclough K, Hum. Mutat. 2013 May; 34(5):669-85). Based on internal structural analysis, this variant may modestly disrupt an important non-specific protein-DNA interaction (Chi YI et al. Mol. Cell, 2002 Nov;10:1129-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
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 rs137853238 with MODY3. -

Monogenic diabetes Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Jun 04, 2015	The c.815G>A (p.(Arg272His)) pathogenic variant in the HNF1A gene has been reported previously in patients with Maturity-Onset Diabetes of the Young, Type 3 (MODY3) (9313763, 11463573, 19150152, 9032114). The variant tracks with disease incidence across multiple generations in multiple families (9032114, AACE report). The c.815G>A variant was not observed in the NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project, or Exome Aggregation Consortium (ExAC) databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, LRT, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. In particular, the c.815G>A variant is located within helix 3 of the homeodomain DNA binding motif, a part of the domain strictly conserved among all known homeodomain sequences (10585442, 15726414). Electrophoretic mobility shift assays showed the p.Arg272His variant has reduced DNA binding activity compared to the normal protein (10585442); ACMG Criteria = PS3, PM1, PM2, PP3, PP5, PP1 -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Jul 05, 2022	The c.815G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to histidine at codon 272 (p.(Arg272His)) of NM_000545.8. This variant resides in an amino acid within the HNF1alpha DNA binding domain that directly binds DNA, which is defined as critical for the protein function by the ClinGen MDEP (PM1). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, this variant was identified in at least 18 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:31166087, PMID:18003757, PMID:24905847, PMID:31483937, PMID:29439679, PMID:23610083, PMID:21989397, PMID:21395678, PMID:21224407, PMID:15114102, ClinVar ID 14931, internal lab contributors). This variant segregated with diabetes, with 13 informative meioses in multiple families with MODY (PP1_Strong; PMID:15114102, internal lab contributors). Functional studies demonstrated the p.Arg272His protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PS3_Supporting; PMID: 16781669). In summary, c.815G>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, PS4, PM1, PP3, PM2_Supporting, PS3_Supporting. -

Type 1 diabetes mellitus 20 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1997

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Aug 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.0	D;.;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.96
MutPred		0.84		Loss of MoRF binding (P = 0.0484);Loss of MoRF binding (P = 0.0484);Loss of MoRF binding (P = 0.0484);Loss of MoRF binding (P = 0.0484);
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.8
gMVP		0.99

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: rs137853238; hg19: chr12-121432068; COSMIC: COSV57460553; COSMIC: COSV57460553;