12-120994229-C-T

Position:

• chr12-120994229-C-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP3 PM2_Supporting PS3_Moderate PM1_Supporting PS4 PP1_Strong PP4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, 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 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 28 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 30760653, 29927023, 30663027, 29207974, 28105082, internal lab contributors). At least two of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, and both were antibody negative and one responded to low dose sulfonylureas) (PP4_Moderate; PMIDs: 30760653, 281505082). This variant segregated with diabetes, with 16 informative meioses in multiple families with MODY (PP1_Strong; PMIDs: 30760653. 28105082, internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Thr260Met protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate; PMID:32910913). In summary, c.779C>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_supporting, PM2_Supporting, PP3, PS4, PP4_Moderate, PP1_Strong, PS3_Moderate. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10588543/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HNF1A NM_000545.8 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 7.49

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.779C>T	p.Thr260Met	missense_variant	4/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.779C>T	p.Thr260Met	missense_variant	4/10
HNF1A	NM_001406915.1	c.779C>T	p.Thr260Met	missense_variant	4/9
HNF1A	XM_024449168.2	c.779C>T	p.Thr260Met	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.779C>T	p.Thr260Met	missense_variant	4/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249268 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

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: 0.00000137 AC: 2 AN: 1461240 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 01, 2021	DNA sequence analysis of the HNF1A gene demonstrated a sequence change, c.779C>T, in exon 4 that results in an amino acid change, p.Thr260Met. This sequence change has been described in gnomAD in one individual in the East Asian subpopulation (dbSNP rs886039544). The p.Thr260Met change affects a highly conserved amino acid residue located in a domain of the HNF1A protein that is known to be functional. The p.Thr260Met substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in multiple individual with MODY (PMID: 9166684, 23607861, 28105082, 15928245, 18003757, 30455330, 9045858). Experimental studies have demonstrated that this sequence change impacts the function of the HNF1A protein (PMID: 30507613, 23607861, 30455330). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 09, 2022	Published functional studies demonstrate that T260M significantly inhibits the normal regulatory effects of HNF1A, and causes increased bile acid synthesis (Ekholm et al., 2013); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22060211, 21224407, 20132997, 18003757, 21170474, 16496320, 30851333, 30663027, 23607861, 9045858, 11058894, 28105082, 9166684, 20393147, 29207974, 28701371, 19754856, 15928245, 12453420, 30760653) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 25, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HNF1A function (PMID: 23607861). 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: 265436). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 9166684, 15928245, 23607861, 28105082, 30663027; Invitae). It has also been observed to segregate with disease in related individuals. 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 sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 260 of the HNF1A protein (p.Thr260Met). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 16, 2018	- -

Maturity onset diabetes mellitus in young Pathogenic:3

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. Sufficient evidence is found to confer the association of this particular variant rs886039544 with MODY3. -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 13, 2020	The p.Thr260Met variant in HNF1A has been reported in 13 individual with MODY, segregated with disease in 3 affected relatives from 1 family (PMID: 21224407, 22060211, 28105082, 28701371, 19754856, 20132997, 9045858, 15928245, 18003757, 23607861), and has been identified in 0.005% (1/18322) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs886039544). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. In vitro functional studies provide some evidence that the p.Thr260Met variant may impact protein function (PMID: 30455330, 30507613, 23607861). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Thr260Met is located in a region of HNF1A that is essential to protein folding and stability, suggesting that this variant is in a functional domain and supports pathogenicity (PMID: 28105082, 12453420). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PS4_moderate, PM1, PM2_supporting, PP3, PP1 (Richards 2015). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2023	Variant summary: HNF1A c.779C>T (p.Thr260Met) 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 allele was found at a frequency of 4e-06 in 249268 control chromosomes. c.779C>T has been reported in the literature as co-segregating with disease in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (example, Lehto_1997). 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 (Ekholm_2013). The most pronounced variant effect results in an abolished activation of the cytochrome P450 7A1 (CYP7A1), Farnesoid X receptor (FXR), Small heterodimeric partner (SHP) and Apical sodium-dependent bile salt transporter (ASBT) promoters in-vitro. Six submitters including the ClinGen Monogenic Diabetes Variant Curation Expert Panel have cited clinical-significance assessments for this variant to ClinVar after 2014. The following publications have been ascertained in the context of this evaluation (PMID: 11942313, 9166684, 10333057, 16496320, 12453420, 17924661, 9045858, 23607861). All submitters classified the variant as pathogenic/likely 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 13, 2022

The c.779C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of threonine to methionine at codon 260 (p.(Thr260Met)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). Additionally, 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 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in at least 28 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PMIDs: 30760653, 29927023, 30663027, 29207974, 28105082, internal lab contributors). At least two of these individuals had a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50% and negative genetic testing for HNF4A, and both were antibody negative and one responded to low dose sulfonylureas) (PP4_Moderate; PMIDs: 30760653, 281505082). This variant segregated with diabetes, with 16 informative meioses in multiple families with MODY (PP1_Strong; PMIDs: 30760653. 28105082, internal lab contributors). A luciferase assay meeting the ClinGen MDEP quality control specifications demonstrated that the p.Thr260Met protein has transactivation activity below 40% of wildtype, indicating that this variant impacts protein function (PS3_Moderate; PMID: 32910913). In summary, c.779C>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_supporting, PM2_Supporting, PP3, PS4, PP4_Moderate, PP1_Strong, PS3_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Pathogenic	0.81	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	-4.6	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		0.98
MutPred		0.84		Gain of MoRF binding (P = 0.0811);Gain of MoRF binding (P = 0.0811);Gain of MoRF binding (P = 0.0811);Gain of MoRF binding (P = 0.0811);
MVP		0.99
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.93

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: rs886039544; hg19: chr12-121432032; COSMIC: COSV57459458; COSMIC: COSV57459458;