NM_000545.8(HNF1A):c.864del (p.Pro291fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000723679.14

Allele description [Variation Report for NM_000545.8(HNF1A):c.864del (p.Pro291fs)]

NM_000545.8(HNF1A):c.864del (p.Pro291fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000545.8(HNF1A):c.864del (p.Pro291fs)

Other names:

NM_000545.6(HNF1A):c.864del; p.Pro291fs

HGVS:

NC_000012.12:g.120994314del
NG_011731.2:g.20569del
NM_000545.8:c.864delMANE SELECT
NM_001306179.2:c.864del
NP_000536.6:p.Pro291fs
NP_001293108.2:p.Pro291fs
LRG_522:g.20569del
NC_000012.11:g.121432115del
NC_000012.11:g.121432117del
NC_000012.12:g.120994314delG
NM_000545.5:c.864delG
NM_000545.6:c.864delG

Protein change:

P291fs

Links:

dbSNP: rs762703502

NCBI 1000 Genomes Browser:

rs762703502

Molecular consequence:

NM_000545.8:c.864del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001306179.2:c.864del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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zinc finger protein 226 isoform a [Homo sapiens]
zinc finger protein 226 isoform a [Homo sapiens]
gi|977357030|ref|NP_057528.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700603	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Dec 23, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25414397, 26287533 Citation Link,
SCV001474911	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Pathogenic (Aug 6, 2020)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25414397, 26287533, 26467025
SCV001780946	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 3, 2023)	germline	clinical testing	Citation Link,
SCV003442077	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15928245, 18003757, 26287533, 28492532

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital.

Delvecchio M, Ludovico O, Menzaghi C, Di Paola R, Zelante L, Marucci A, Grasso V, Trischitta V, Carella M, Barbetti F, Gallo F, Coccioli MS, Zecchino C, Faienza MF, Cardinale G, Franzese A, Mozzillo E, Iafusco D, Zanfardino A.

Diabetes Care. 2014 Dec;37(12):e258-60. doi: 10.2337/dc14-1788. No abstract available.

PubMed [citation]

PMID:: 25414397

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (6)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000700603.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

#	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		2	not provided	not provided	not provided

From Athena Diagnostics, SCV001474911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.

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

From GeneDx, SCV001780946.4

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

Description

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: 9313763, 17054605, 30476138, 26287533, 33535453, 34587721, 35112188, 25414397)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003442077.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Pro291Glnfs*51) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 26287533). ClinVar contains an entry for this variant (Variation ID: 435424). For these reasons, this variant has been classified as Pathogenic.

#	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: Oct 13, 2024

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