rs1555212359

Variant names:

• chr12-120997522-GC-G
• rs1555212359
• NM_000545.8:c.1359delC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1359del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 454 (NM_000545.8), adding 3 novel amino acids before encountering a stop codon (p.(Ser454AlafsTer3)). This variant, located in biologically-relevant exon 7 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 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.1359del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645372549/MONDO:0015967/017

• Frequency: Genomes: not found (cov: 32)
• Consequence: HNF1A NM_000545.8 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.507
• Publications: 0 publications found

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]

HNF1A Gene-Disease associations (from GenCC):

• monogenic diabetes

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• type 1 diabetes mellitus 20

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp
• diabetes mellitus, noninsulin-dependent

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• maturity-onset diabetes of the young type 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hyperinsulinism due to HNF1A deficiency

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• nonpapillary renal cell carcinoma

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1359delC	p.Ser454AlafsTer3	frameshift_variant	Exon 7 of 10	ENST00000257555.11	NP_000536.6
HNF1A	NM_001306179.2	c.1359delC	p.Ser454AlafsTer3	frameshift_variant	Exon 7 of 10		NP_001293108.2
HNF1A	XM_024449168.2	c.1359delC	p.Ser454AlafsTer3	frameshift_variant	Exon 7 of 9		XP_024304936.1
HNF1A	NM_001406915.1	c.1309+781delC		intron_variant	Intron 6 of 8		NP_001393844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNF1A	ENST00000257555.11	c.1359delC	p.Ser454AlafsTer3	frameshift_variant	Exon 7 of 10	1	NM_000545.8	ENSP00000257555.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Monogenic diabetes Pathogenic:1

Jul 24, 2025

ClinGen Monogenic Diabetes Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1359del variant in the HNF1 homeobox A gene, HNF1A, causes a frameshift in the protein at codon 454 (NM_000545.8), adding 3 novel amino acids before encountering a stop codon (p.(Ser454AlafsTer3)). This variant, located in biologically-relevant exon 7 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 and v4.1.0 (PM2_Supporting). This variant was identified in an individual with a clinical history suggestive of HNF1A-MODY (MODY probability calculator result >50%); however, HNF4A was not tested (internal lab contributors). In summary, c.1359del meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 6/30/2025): PVS1, PM2_Supporting. -

Maturity onset diabetes mellitus in young Pathogenic:1

-

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 rs1555212359 with MODY3. -

not provided Pathogenic:1

Jun 10, 2022

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 has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual tested at Athena Diagnostics with clinical features associated with this gene. -

Maturity-onset diabetes of the young type 3 Pathogenic:1

Jul 31, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.51
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1555212359; hg19: chr12-121435325;