NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 24, 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:: RCV000494442.14

Allele description [Variation Report for NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)]

NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

12q24.31

Genomic location:

Preferred name:

NM_000545.8(HNF1A):c.475C>T (p.Arg159Trp)

Other names:

NM_000545.6(HNF1A):c.475C>T; p.Arg159Trp

HGVS:

NC_000012.12:g.120988981C>T
NG_011731.2:g.15236C>T
NM_000545.8:c.475C>TMANE SELECT
NM_001306179.2:c.475C>T
NP_000536.5:p.Arg159Trp
NP_000536.6:p.Arg159Trp
NP_001293108.2:p.Arg159Trp
LRG_522t1:c.475C>T
LRG_522:g.15236C>T
NC_000012.11:g.121426784C>T
NC_000012.11:g.121426784C>T
NM_000545.5:c.475C>T
NM_000545.6:c.475C>T

Protein change:

R159W

Links:

dbSNP: rs765432081

NCBI 1000 Genomes Browser:

rs765432081

Molecular consequence:

NM_000545.8:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000582396	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 28, 2022)	germline	clinical testing	Citation Link,
SCV003442075	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9097962, 9075818, 9754819, 12050210, 18672310, 27083284, 30191644, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000582396

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 28, 2022)

germline

clinical testing

Citation Link,

SCV003442075

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of nine novel mutations in the hepatocyte nuclear factor 1 alpha gene associated with maturity-onset diabetes of the young (MODY3).

Vaxillaire M, Rouard M, Yamagata K, Oda N, Kaisaki PJ, Boriraj VV, Chevre JC, Boccio V, Cox RD, Lathrop GM, Dussoix P, Philippe J, Timsit J, Charpentier G, Velho G, Bell GI, Froguel P.

Hum Mol Genet. 1997 Apr;6(4):583-6.

PubMed [citation]

PMID:: 9097962

Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.

Frayling TM, Bulamn MP, Ellard S, Appleton M, Dronsfield MJ, Mackie AD, Baird JD, Kaisaki PJ, Yamagata K, Bell GI, Bain SC, Hattersley AT.

Diabetes. 1997 Apr;46(4):720-5.

PubMed [citation]

PMID:: 9075818

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000582396.5

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 9754819, 12453420, 28410371, 28012402, 11058894, 30191644, 31264968, 33538814, 18003757, 34440499, 34556497, 9075818, 9097962, 23548576)

#	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, SCV003442075.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg159 amino acid residue in HNF1A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9097962). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 429750). This missense change has been observed in individuals with diabetes (PMID: 9075818, 9754819, 12050210, 18672310, 27083284, 30191644). 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 sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the HNF1A protein (p.Arg159Trp).

#	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 8, 2024

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