rs1057524908

chr12-120993686-G-GC

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.694dup(p.Leu232ProfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T231T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:2 O:1
• Conservation: PhyloP100: -0.290

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 12-120993686-G-GC is Pathogenic according to our data. Variant chr12-120993686-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 393456.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNF1A	NM_000545.8	c.694dup	p.Leu232ProfsTer7	frameshift_variant	3/10	ENST00000257555.11
HNF1A	NM_001306179.2	c.694dup	p.Leu232ProfsTer7	frameshift_variant	3/10
HNF1A	NM_001406915.1	c.694dup	p.Leu232ProfsTer7	frameshift_variant	3/9
HNF1A	XM_024449168.2	c.694dup	p.Leu232ProfsTer7	frameshift_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNF1A	ENST00000257555.11	c.694dup	p.Leu232ProfsTer7	frameshift_variant	3/10	1	NM_000545.8	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Translational Genomics Laboratory, University of Maryland School of Medicine	Sep 09, 2016	The c.694dupC variant in codon 232 (exon 3) of the HNF1 homeobox A gene, HNF1A, results in a frame shifting change in the protein with Leucine-232 as the first affected amino acid. The c. 694dupC variant was not observed in the NHLBI Exome Sequencing Project (ESP), 1000 Genomes Project, or Exome Aggregation Consortium (ExAC) databases. Loss of function frameshift and nonsense mutations in the HNF1A gene, including ones in exon 3, have been reported previously in patients with Maturity-Onset Diabetes of the Young, Type 3 (MODY3) (11058894, 11463573, 23348805). Frameshift mutations in exon 3 would be expected to interrupt the DNA binding domain of the HNF1A protein (18003757). This result is consistent with the patient's clinical diagnosis of MODY. ACMG Criteria = PVS1, PM2, PP4 -
Pathogenic, reviewed by expert panel	curation	ClinGen Monogenic Diabetes Variant Curation Expert Panel	Apr 12, 2022	The c.694dup variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 232 of NM_000545.8, adding 7 novel amino acids before encountering a stop codon (p.Leu232ProfsTer7). This variant, located in biologically-relevant exon 3 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 also absent from gnomAD v2.1.1 (PM2_Supporting). 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.694dup 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): PVS1, PM2_Supporting, PP4_Moderate. -

Maturity onset diabetes mellitus in young Other:1

Uncertain risk allele, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

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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 rs1057524908 with MODY3. -

Computational scores

Source: dbNSFP v4.3

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: rs1057524908; hg19: chr12-121431489;