NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Dec 22, 2023
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:: RCV001780195.13

Allele description [Variation Report for NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr)]

NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr)

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.1135C>A (p.Pro379Thr)

Other names:

NM_000545.8(HNF1A):c.1135C>A; p.Pro379Thr

HGVS:

NC_000012.12:g.120996568C>A
NG_011731.2:g.22823C>A
NM_000545.8:c.1135C>AMANE SELECT
NM_001306179.2:c.1135C>A
NP_000536.6:p.Pro379Thr
NP_001293108.2:p.Pro379Thr
LRG_522t1:c.1135C>A
LRG_522:g.22823C>A
NC_000012.11:g.121434371C>A
NC_000012.11:g.121434371C>A
NM_000545.5:c.1135C>A
NM_000545.6:c.1135C>A
NM_001306179.1:c.1135C>A

Protein change:

P379T

Links:

dbSNP: rs754729248

NCBI 1000 Genomes Browser:

rs754729248

Molecular consequence:

NM_000545.8:c.1135C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001306179.2:c.1135C>A - 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
SCV002238128	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 22, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 18003757, 21683639, 22808921, 23348805, 23803251, 25935773, 26479152, 28012402, 28170077, 30293189, 28492532
SCV002770443	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Mar 22, 2023)	unknown	clinical testing	PubMed (18) [See all records that cite these PMIDs] 30293189, 26479152, 28012402, 28170077, 32910913, 18003757, 25935773, 36208030, 22808921, 35673428, 24069322, 26110317, 32238361, 23674172, 23803251, 28410371, 21683639, 26467025
SCV004035627	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 18, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002238128

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 22, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002770443

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Mar 22, 2023)

unknown

clinical testing

PubMed (18)
[See all records that cite these PMIDs]

SCV004035627

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 18, 2023)

germline

clinical testing

Citation Link

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

Citations

PubMed

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia.

Colclough K, Bellanne-Chantelot C, Saint-Martin C, Flanagan SE, Ellard S.

Hum Mutat. 2013 May;34(5):669-85. doi: 10.1002/humu.22279. Epub 2013 Apr 2.

PubMed [citation]

PMID:: 23348805

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (20)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002238128.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 379 of the HNF1A protein (p.Pro379Thr). This variant is present in population databases (rs754729248, gnomAD 0.01%). This missense change has been observed in individuals with maturity-onset diabetes of the young (PMID: 18003757, 21683639, 22808921, 23348805, 23803251, 25935773, 26479152, 28012402, 28170077, 30293189). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 972818). 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 not expected to disrupt HNF1A protein function with a negative predictive value of 80%. 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

From Athena Diagnostics, SCV002770443.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (18)

Description

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene and appears to segregate with disease in multiple families (personal communication from ClinGen Monogenic Diabetes Expert Panel). At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Computational tools predict that this variant is damaging.

#	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, SCV004035627.1

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32910913, 18003757, 21224407, 28170077, 23348805, 36208343, 34108472, 28012402, 21683639, 16917892, 26479152, 15883474, 15657605, 36208030, 30293189)

#	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

Last Updated: Oct 13, 2024

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