rs1555212248

Variant names:

• chr12-120996569-CT-C
• rs1555212248
• NM_000545.8:c.1137delT

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS4 PP1_Strong PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1137del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.Val380SerfsTer4). This variant, located in biologically-relevant exon 6 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). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID:33538814, internal lab contributors). This variant also segregated with diabetes, with 5 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1137del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong LINK:https://erepo.genome.network/evrepo/ui/classification/CA645372923/MONDO:0015967/017

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: -4.49

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 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HNF1A	NM_000545.8	c.1137delT	p.Val380SerfsTer4	frameshift_variant	Exon 6 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1137delT	p.Val380SerfsTer4	frameshift_variant	Exon 6 of 10		NP_001293108.2
HNF1A	NM_001406915.1	c.1137delT	p.Val380SerfsTer4	frameshift_variant	Exon 6 of 9		NP_001393844.1
HNF1A	XM_024449168.2	c.1137delT	p.Val380SerfsTer4	frameshift_variant	Exon 6 of 9		XP_024304936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1137delT	p.Val380SerfsTer4	frameshift_variant	Exon 6 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461666 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Maturity onset diabetes mellitus in young Pathogenic:3

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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 rs1555212248 with MODY3. -

Feb 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1137delT pathogenic mutation, located in coding exon 6 of the HNF1A gene, results from a deletion of one nucleotide at nucleotide position 1137, causing a translational frameshift with a predicted alternate stop codon (p.V380Sfs*4). This variant (also referred to as P379fsdelT) was reported in individual(s) with features consistent with maturity-onset diabetes of the young (MODY) (Hansen T, Diabetes 1997 Apr; 46(4):726-30; Chèvre JC, Diabetologia 1998 Sep; 41(9):1017-23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Jul 30, 2018

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1137delT (p.Val380Serfs*4) pathogenic variant is located in exon 6 of the HNF1A gene. The deletion of one nucleotide causes a translational frameshift. The first amino acid altered is at position 380 of the protein, in which serine replaces valine, and there is a premature stop codon 4 amino acids downstream of this altered amino acid. This variant has been reported as pathogenic in the literature by our lab (PMID: 25555642) and others (PMID: 9075819). This variant has not been observed in the general population despite 245,334 alleles being tested (Genome Aggregation Database). Heterozygous inactivating variants in HNF1A are well-described in the medical literature and account for 30-65% of patients with a MODY phenotype (https://www.ncbi.nlm.nih.gov/books/NBK500456/). In summary, this variant is interpreted as pathogenic. -

not provided Pathogenic:3

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Val380Serfs*4) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 9075819). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this HNF1A variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 34,079 individuals referred to our laboratory for HNF1A testing. ClinVar contains an entry for this variant (Variation ID: 435426). For these reasons, this variant has been classified as Pathogenic. -

Oct 29, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -

Sep 03, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9754819, 33852230, 25555642, 15928245, 11058894, 35089870, 34789499, 35328643, 36227502, 36257325, 9075819) -

Maturity-onset diabetes of the young type 3 Pathogenic:2

Jun 08, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val380Serfs*4 variant leads to a frameshift followed by a premature termination codon after four amino acids. The variant falls within exon 6 of 10 total exons and is predicted to cause loss-of-function. This variant has been reported in multiple unrelated individuals with HNF1A-related MODY (PMID: 9075819, PMID: 33852230, PMID: 36227502, PMID: 36257325). The p.Val380Serfs*4 variant is absent from large population studies (gnomAD v2.1.1). Loss-of-function is a known pathogenic mechanism of HNF1A-related MODY. -

Monogenic diabetes Pathogenic:1

Dec 31, 2021

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1137del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 380 (NM_000545.8), adding 4 novel amino acids before encountering a stop codon (p.Val380SerfsTer4). This variant, located in biologically-relevant exon 6 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). Also, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in at least 17 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 33538814, internal lab contributors). This variant also segregated with diabetes, with 5 informative meioses in 3 families with MODY (PP1_Strong; internal lab contributors). In summary, c.1137del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0, approved 6/4/2021): PVS1, PM2_Supporting, PS4, PP1_Strong -

HNF1A-related disorder Pathogenic:1

May 18, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HNF1A c.1137delT variant is predicted to result in a frameshift and premature protein termination (p.Val380Serfs*4). This variant has been reported to be pathogenic for maturity onset diabetes of the young (MODY) (Pro379fs in M2 Pedigree at Hansen et al. 1997. PubMed ID: 9075819). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in HNF1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1555212248; hg19: chr12-121434372;