12-120994261-C-T

Position:

• chr12-120994261-C-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.811C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 271 (p.(Arg271Trp) of transcript, e.g. NM_000545.8. This variant was identified in over 26 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with at least four informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated the p.Arg271Trp protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID:21170474) (PS3_Supporting). 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). Another missense variant, c. 812G>A (p.Arg271Gln), has been interpreted as pathogenic by the ClinGen MDEP and p. Arg271Trp has a greater Grantham distance (PM5). The variant was identified in at least 8 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate). This variant failed QC in gnomAD v2.1.1. The variant was absent other than two heterozygotes filtered out due to poor quality which even if real would place the frequency below the ClinGen MDEP cutoff for PM2_Supporting (PM2_Supporting). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.814C>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): PS4, PP1_Strong, PS3_Supporting, PM1, PM5, PP4_Moderate, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10588544/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:7
• Conservation: PhyloP100: 2.82

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.811C>T	p.Arg271Trp	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.811C>T	p.Arg271Trp	missense_variant	4/10
HNF1A	NM_001406915.1	c.811C>T	p.Arg271Trp	missense_variant	4/9
HNF1A	XM_024449168.2	c.811C>T	p.Arg271Trp	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.811C>T	p.Arg271Trp	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461136 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726834

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2023	Published functional studies demonstrate a damaging effect on affinity, DNA binding, and transcriptional activity (Galn et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reliable data are not available in large population cohorts to assess the frequency of this variant in publicly available databases.; This variant is associated with the following publications: (PMID: 20393147, 18838325, 21051477, 33459938, 31264968, 9754819, 21170474, 26853433, 12574234, 16274290, 12453420, 16562587, 16249556, 11058894, 35592779, 34746319, 18003757) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Mar 14, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 12488961, 12574234, 21170474). 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: 265193). This missense change has been observed in individuals with clinical features of HNF1A-related conditions and/or clinical features of HNF1A-related disorders (PMID: 9754819, 12488961, 12574234, 15928245, 16249556, 16562587, 21170474, 31264968). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 271 of the HNF1A protein (p.Arg271Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 16, 2020	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.811C>T, in exon 4 that results in an amino acid change, p.Arg271Trp. This sequence change has been previously described in a family with MODY (PMID: 9754819). Functional studies showed that this variant impairs HNF1A activity; it had an impact on DNA binding with decrease in both affinity and maximal binding (PMID: 21170474). This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP rs886039386). The p.Arg271Trp change affects a highly conserved amino acid residue located in the DNA recognition domain (homeodomain) of the DNA binding region of the HNF1A protein which is known to be functional. The p.Arg271Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). The p.Arg271Trp amino acid change occurs in a region of the HNF1A gene where other missense sequence changes have been described in patients with HNF1A-related MODY. -

Maturity onset diabetes mellitus in young Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 11, 2016	The p.R271W pathogenic mutation (also known as c.811C>T), located in coding exon 4 of the HNF1A gene, results from a C to T substitution at nucleotide position 811. The arginine at codon 271 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was first described to segregate with disease in a French MODY kindred (Ch&egrave;vre JC et al. Diabetologia, 1998 Sep;41:1017-23). It has subsequently been reported in additional MODY patients, including as a de novo occurrence in one individual, paternity confirmed (Malecki MT et al. Diabetes Care, 2005 Nov;28:2774-6). In vitro studies using HeLa cells showed that the p.R271W mutation results in abnormal localization of the mutant protein and a significant reduction (p<0.01) in transactivation activity as compared to wild-type (Bj&oslash;rkhaug L et al. J. Clin. Endocrinol. Metab., 2003 Feb;88:920-31). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2023	Variant summary: HNF1A c.811C>T (p.Arg271Trp) results in a non-conservative amino acid change located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249290 control chromosomes. c.811C>T has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity in its ability to activate transcription using a luciferase reporter gene (example, PMID 12574234). The following publications have been ascertained in the context of this evaluation (PMID: 9754819, 12574234, 10333057, 12488961, 11058894, 16562587, 16274290, 12453420, 18838325). Five clinical diagnostic laboratories and the ClinGen Monogenic Diabetes Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 14, 2022

The c.811C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to tryptophan at codon 271 (p.(Arg271Trp) of transcript, e.g. NM_000545.8. This variant was identified in over 26 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; internal lab contributors). Additionally, this variant segregated with diabetes, with at least four informative meioses in multiple families with MODY (PP1_Strong; internal lab contributors). Functional studies demonstrated the p.Arg271Trp protein has transactivation below 40% of wildtype, indicating that this variant impacts protein function (PMID: 21170474) (PS3_Supporting). 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). Another missense variant, c. 812G>A (p.Arg271Gln), has been interpreted as pathogenic by the ClinGen MDEP and p. Arg271Trp has a greater Grantham distance (PM5). The variant was identified in at least 8 individuals with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and autoantibody negative) (PP4_Moderate). This variant failed QC in gnomAD v2.1.1. The variant was absent other than two heterozygotes filtered out due to poor quality which even if real would place the frequency below the ClinGen MDEP cutoff for PM2_Supporting (PM2_Supporting). Lastly, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.93, which is greater than the MDEP VCEP threshold of 0.70 (PP3) and is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.814C>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): PS4, PP1_Strong, PS3_Supporting, PM1, PM5, PP4_Moderate, PP3, PM2_Supporting. -

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	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.93	.;D;D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.2	D;.;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	.;.;.;D
Vest4		0.99
MutPred		0.79		Loss of disorder (P = 0.0474);Loss of disorder (P = 0.0474);Loss of disorder (P = 0.0474);Loss of disorder (P = 0.0474);
MVP		1.0
MPC		2.2
ClinPred		0.99	D
GERP RS		3.9
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: rs886039386; hg19: chr12-121432064; COSMIC: COSV57462472; COSMIC: COSV57462472;