12-120989017-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000545.8(HNF1A):c.511C>T(p.Arg171Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: HNF1A NM_000545.8 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:5
• Conservation: PhyloP100: 1.57

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-120989017-C-T is Pathogenic according to our data. Variant chr12-120989017-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 377965.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-120989017-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.511C>T	p.Arg171Ter	stop_gained	2/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.511C>T	p.Arg171Ter	stop_gained	2/10
HNF1A	NM_001406915.1	c.511C>T	p.Arg171Ter	stop_gained	2/9
HNF1A	XM_024449168.2	c.511C>T	p.Arg171Ter	stop_gained	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.511C>T	p.Arg171Ter	stop_gained	2/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 15, 2021	This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Studies show that this variant results in reduced transactivation activity as well as loss of DNA binding activity (PMID: 10585442, 12107757, 12530534, 12574234). The variant is located in a region that is considered important for protein function and/or structure. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2022	Published functional studies demonstrate reduced DNA binding ability, transactivation potential and impaired mRNA stability (Thomas et al., 2002); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29439679, 9097962, 12574234, 27420379, 26641800, 12530534) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 24, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 377965). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young 3 (PMID: 9097962). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg171*) in the HNF1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HNF1A are known to be pathogenic (PMID: 15928245, 18003757). -

Maturity onset diabetes mellitus in young Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2017

The p.R171* pathogenic mutation (also known as c.511C>T), located in coding exon 2 of the HNF1A gene, results from a C to T substitution at nucleotide position 511. This changes the amino acid from an arginine to a stop codon within coding exon 2. This mutation has been observed to co-segregate with disease in families with maturity-onset diabetes of the young (MODY) (Vaxillaire M et al, Hum. Mol. Genet. 1997; 6(4):583-6; Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31) and has been reported in multiple proband's with a MODY phenotype (Bennett JT et al. Mol. Genet. Metab., 2015 Mar;114:451-8; de Santana LS et al. Clin. Genet., 2017 Feb; [Epub ahead of print]). Functional studies demonstrated that this mutation significantly decreases transcriptional activity and results in the absence of DNA binding ability (Bjørkhaug et al, J. Clin. Endocrinol. Metab. 2003; 88(2):920-31). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Monogenic diabetes Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Apr 10, 2022

The c.511C>T variant in the HNF1 homeobox A gene, HNF1A, results in a premature termination at codon 171 (p.(Arg171Ter)) of NM_000545.8. This variant, located in biologically-relevant exon 2 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 23348805). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes, with 13 informative meioses in 5 families with MODY (PP1_Strong; internal lab contributors). This variant was identified in 14 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 9097962, 10102714, 12530534, 12574234, internal lab contributors). 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 negative antibodies) (PP4_Moderate; internal lab contributors). In summary, c.511C>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 September 30, 2021): PVS1, PS4, PP1_Strong, PM2_Supporting, PP4_Moderate. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	51
Dann	Uncertain	1.0
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Benign	0.76	D
MutationTaster	Benign	1.0	A;A;A;A;A
Vest4		0.97
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.31		Position offset: -17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1057520291; hg19: chr12-121426820; COSMIC: COSV57458707;