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NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys) AND not provided

Germline classification:
Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:
Mar 3, 2022
Review status:
criteria provided, conflicting classifications
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:
RCV000994997.23

Allele description [Variation Report for NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys)]

NM_000545.8(HNF1A):c.142G>A (p.Glu48Lys)

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.142G>A (p.Glu48Lys)
Other names:
NM_001306179.1:c.142G>A
HGVS:
  • NC_000012.12:g.120978910G>A
  • NG_011731.2:g.5165G>A
  • NM_000545.8:c.142G>AMANE SELECT
  • NM_001306179.2:c.142G>A
  • NP_000536.6:p.Glu48Lys
  • NP_001293108.2:p.Glu48Lys
  • LRG_522t1:c.142G>A
  • LRG_522:g.5165G>A
  • NC_000012.11:g.121416713G>A
  • NC_000012.11:g.121416713G>A
  • NM_000545.5:c.142G>A
  • NM_000545.6:c.142G>A
Protein change:
E48K
Links:
dbSNP: rs772222326
NCBI 1000 Genomes Browser:
rs772222326
Molecular consequence:
  • NM_000545.8:c.142G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306179.2:c.142G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001801304GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely benign
(Mar 18, 2021)
germlineclinical testing

Citation Link,

SCV002009080Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain significance
(Nov 3, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002221833Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Mar 3, 2022)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes.

Møller AM, Dalgaard LT, Pociot F, Nerup J, Hansen T, Pedersen O.

Diabetologia. 1998 Dec;41(12):1528-31.

PubMed [citation]
PMID:
9867222
See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV001801304.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32910913, 15928245, 27899486, 9867222, 24097065, 23274891, 30455330)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002009080.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV002221833.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 48 of the HNF1A protein (p.Glu48Lys). This variant is present in population databases (rs772222326, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of HNF1A-related conditions (PMID: 9867222, 15928245, 23274891). ClinVar contains an entry for this variant (Variation ID: 806957). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HNF1A protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on HNF1A function (PMID: 27899486). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 23, 2024