NM_000545.8(HNF1A):c.399_405del (p.Val134fs) AND Monogenic diabetes

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 24, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002260480.1

Allele description [Variation Report for NM_000545.8(HNF1A):c.399_405del (p.Val134fs)]

NM_000545.8(HNF1A):c.399_405del (p.Val134fs)

Gene:

HNF1A:HNF1 homeobox A [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000545.8(HNF1A):c.399_405del (p.Val134fs)

Other names:

NM_001306179.2:c.399_405del

HGVS:

NC_000012.12:g.120988905_120988911del
NG_011731.2:g.15160_15166del
NM_000545.8:c.399_405delMANE SELECT
NM_001306179.2:c.399_405del
NP_000536.6:p.Val134fs
NP_001293108.2:p.Val134fs
LRG_522:g.15160_15166del
NC_000012.11:g.121426708_121426714del

Protein change:

V134fs

Links:

dbSNP: rs2135832615

NCBI 1000 Genomes Browser:

rs2135832615

Molecular consequence:

NM_000545.8:c.399_405del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001306179.2:c.399_405del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Monogenic diabetes
Identifiers:: MONDO: MONDO:0015967; MedGen: C3888631

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002540105	ClinGen Monogenic Diabetes Variant Curation Expert Panel	reviewed by expert panel (ClinGen Diabetes ACMG Specifications v1 1)	Likely pathogenic (Jun 24, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002540105

ClinGen Monogenic Diabetes Variant Curation Expert Panel

reviewed by expert panel

(ClinGen Diabetes ACMG Specifications v1 1)

Likely pathogenic
(Jun 24, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen Monogenic Diabetes Variant Curation Expert Panel, SCV002540105.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.399_405del variant in the HNF1 Homeobox A gene, HNF1A, causes a frameshift in the protein at codon 134 of NM_000545.8, adding 19 novel amino acids before encountering a stop codon (p.(Val134ProfsTer19)). 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 in absent in gnomAD v2.1.1 (PM2_Supporting). In summary, the c.399_405del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/21): PVS1, PM2_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 24, 2023

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