The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting.
ClinVar Genomic variation as it relates to human health
NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Uncertain significance
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000545.8(HNF1A):c.1135C>A (p.Pro379Thr)
Variation ID: 972818 Accession: VCV000972818.19
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q24.31 12: 120996568 (GRCh38) [ NCBI UCSC ] 12: 121434371 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 19, 2020 Oct 8, 2024 Aug 14, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000545.8:c.1135C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000536.6:p.Pro379Thr missense NM_001306179.2:c.1135C>A NP_001293108.2:p.Pro379Thr missense NC_000012.12:g.120996568C>A NC_000012.11:g.121434371C>A NG_011731.2:g.22823C>A LRG_522:g.22823C>A LRG_522t1:c.1135C>A - Protein change
- P379T
- Other names
-
NM_000545.8(HNF1A):c.1135C>A
p.Pro379Thr
- Canonical SPDI
- NC_000012.12:120996567:C:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| HNF1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
922 | 1014 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Mar 22, 2022 | RCV001249082.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jan 7, 2020 | RCV001293984.3 | |
| Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Dec 22, 2023 | RCV001780195.13 | |
| Uncertain significance (1) |
reviewed by expert panel
|
Aug 14, 2023 | RCV003325992.4 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Nov 6, 2020 | RCV004017808.2 | |
|
HNF1A-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 12, 2024 | RCV004753255.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 14, 2023)
|
reviewed by expert panel
Method: curation
|
Monogenic diabetes
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Monogenic Diabetes Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV004032120.1 First in ClinVar: Sep 09, 2023 Last updated: Sep 09, 2023 |
Comment:
The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. … (more)
The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting. (less)
|
|
|
Uncertain significance
(Jan 07, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Type 1 diabetes mellitus 20
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001482725.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
|
|
|
Pathogenic
(Jan 22, 2020)
|
criteria provided, single submitter
Method: curation
|
Maturity-onset diabetes of the young type 3
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV001423038.2
First in ClinVar: Jul 19, 2020 Last updated: Feb 01, 2022 |
Comment:
The p.Pro379Thr variant in HNF1A has been reported in 10 individuals with maturity-onset diabetes of the young, segregated with disease in 9 affected relatives from … (more)
The p.Pro379Thr variant in HNF1A has been reported in 10 individuals with maturity-onset diabetes of the young, segregated with disease in 9 affected relatives from 3 families (PMID: 30293189, 21683639, 26479152, 28012402), and has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Thr have been reported in association with disease in the literature (PMID: 23348805, 16917892). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Arg and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 23348805, 16917892, 15883474). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease, location in a mutation hotspot, and two likely pathogenic variants that affect the same amino acid. ACMG/AMP Criteria applied: PP1_Strong, PM1, PM5, PP3, PS4_Supporting (Richards 2015). (less)
|
|
|
Uncertain significance
(Mar 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity-onset diabetes of the young type 3
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002318638.1
First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022 |
Comment:
Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of … (more)
Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967>=0.6). A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hyperglycemia (present)
Zygosity: Single Heterozygote
|
|
|
Uncertain significance
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004035627.1
First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023 |
Comment:
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, … (more)
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) (less)
|
|
|
Likely pathogenic
(Mar 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV002770443.2
First in ClinVar: Dec 31, 2022 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Dec 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002238128.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
|
|
|
Likely Pathogenic
(Nov 06, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Maturity onset diabetes mellitus in young
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848489.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Pro379Thr variant in HNF1A has been reported in at least 10 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in … (more)
The p.Pro379Thr variant in HNF1A has been reported in at least 10 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 6 affected relatives from 3 families (Wang 2019 PMID: 30293189, Kyithar 2011 21683639, Bacon 2016 26479152, Giuffrida 2017 28012402, Santana 2017 PMID: 28170077, Bellanné-Chantelot 2008 PMID: 18003757). It has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro379 codon is one of the most frequently mutated sites in the HNF1A gene (Ellard and Colclough 2013 PMID: 23348805). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Moderate, PM1, PP3, PS4_Moderate. (less)
|
|
|
Pathogenic
(Mar 12, 2024)
|
no assertion criteria provided
Method: clinical testing
|
HNF1A-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005365581.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The HNF1A c.1135C>A variant is predicted to result in the amino acid substitution p.Pro379Thr. This variant has been reported to be causative for maturity onset … (more)
The HNF1A c.1135C>A variant is predicted to result in the amino acid substitution p.Pro379Thr. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) (Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Wang et al. 2018. PubMed ID: 30293189; Goodrich et al. 2021. PubMed ID: 34108472. Supp Data 5). Of note, Goodrich et al. showed that this variant may have reduced penetrance. In addition, different missense substitutions at the same codon (p.Pro379Ala, p.Pro379Ser, Pro379His, Pro379Arg) have also been reported to be pathogenic for MODY (Dominguez-Lopez et al. 2005. PubMed ID: 15883474; Xu et al. 2005. PubMed ID: 15657605; Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Ekholm et al. 2013. PubMed ID: 23607861). Therefore, we classify the c.1135C>A (p.Pro379Thr) variant in this patient as pathogenic. (less)
|
Comment:
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The p.Pro379Thr variant in HNF1A has been reported in 10 individuals with maturity-onset diabetes of the young, segregated with disease in 9 affected relatives from 3 families (PMID: 30293189, 21683639, 26479152, 28012402), and has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Thr have been reported in association with disease in the literature (PMID: 23348805, 16917892). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Arg and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 23348805, 16917892, 15883474). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease, location in a mutation hotspot, and two likely pathogenic variants that affect the same amino acid. ACMG/AMP Criteria applied: PP1_Strong, PM1, PM5, PP3, PS4_Supporting (Richards 2015).
Comment:
Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967>=0.6). A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
The p.Pro379Thr variant in HNF1A has been reported in at least 10 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 6 affected relatives from 3 families (Wang 2019 PMID: 30293189, Kyithar 2011 21683639, Bacon 2016 26479152, Giuffrida 2017 28012402, Santana 2017 PMID: 28170077, Bellanné-Chantelot 2008 PMID: 18003757). It has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro379 codon is one of the most frequently mutated sites in the HNF1A gene (Ellard and Colclough 2013 PMID: 23348805). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Moderate, PM1, PP3, PS4_Moderate.
Comment:
The HNF1A c.1135C>A variant is predicted to result in the amino acid substitution p.Pro379Thr. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) (Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Wang et al. 2018. PubMed ID: 30293189; Goodrich et al. 2021. PubMed ID: 34108472. Supp Data 5). Of note, Goodrich et al. showed that this variant may have reduced penetrance. In addition, different missense substitutions at the same codon (p.Pro379Ala, p.Pro379Ser, Pro379His, Pro379Arg) have also been reported to be pathogenic for MODY (Dominguez-Lopez et al. 2005. PubMed ID: 15883474; Xu et al. 2005. PubMed ID: 15657605; Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Ekholm et al. 2013. PubMed ID: 23607861). Therefore, we classify the c.1135C>A (p.Pro379Thr) variant in this patient as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The c.1136C>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to threonine at codon 379 (p.(Pro379Thr)) of NM_000545.6. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00003898, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in 13 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMIDs 21170474, 15657605, internal lab contributors). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50% and negative genetic testing for HNF4A (PP4; internal lab contributor). This variant segregated with diabetes, with at least 4 informative meioses in 3 families (PP1_Strong; internal lab contributors). Another missense variant, c.1136C>G p.Pro379Arg, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Pro379Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): BS1, PP3, PP4, PP1_Strong, PM5_Supporting.
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Comment:
The p.Pro379Thr variant in HNF1A has been reported in 10 individuals with maturity-onset diabetes of the young, segregated with disease in 9 affected relatives from 3 families (PMID: 30293189, 21683639, 26479152, 28012402), and has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754729248). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. The number of reported affected individuals with this variant is slightly greater than expected compared to non-affected individuals with this variant. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Pro379Thr have been reported in association with disease in the literature (PMID: 23348805, 16917892). Two additional likely pathogenic variants, resulting in a different amino acid change at the same position, p.Pro379Arg and p.Pro379His, have been reported in association with disease in the literature, supporting that a change at this position may not be tolerated (PMID: 23348805, 16917892, 29666556, 15657605, 23348805, 16917892, 15883474). In summary, this variant meets criteria to be classified as pathogenic for maturity-onset diabetes of the young in an autosomal dominant manner based on segregation with disease, location in a mutation hotspot, and two likely pathogenic variants that affect the same amino acid. ACMG/AMP Criteria applied: PP1_Strong, PM1, PM5, PP3, PS4_Supporting (Richards 2015).
Comment:
Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:18003757,18003757,15883474,15657605). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.967>=0.6). A missense variant is a common mechanism . Therefore, this variant is classified as uncertain significance according to the recommendation of ACMG/AMP guideline.
Comment:
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)
Comment:
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.
Comment:
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.
Comment:
The p.Pro379Thr variant in HNF1A has been reported in at least 10 individuals with maturity-onset diabetes of the young (MODY) and segregated with disease in at least 6 affected relatives from 3 families (Wang 2019 PMID: 30293189, Kyithar 2011 21683639, Bacon 2016 26479152, Giuffrida 2017 28012402, Santana 2017 PMID: 28170077, Bellanné-Chantelot 2008 PMID: 18003757). It has been identified in 0.011% (4/35382) of Latino chromosomes and 0.002% (3/128426) European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The p.Pro379 codon is one of the most frequently mutated sites in the HNF1A gene (Ellard and Colclough 2013 PMID: 23348805). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PP1_Moderate, PM1, PP3, PS4_Moderate.
Comment:
The HNF1A c.1135C>A variant is predicted to result in the amino acid substitution p.Pro379Thr. This variant has been reported to be causative for maturity onset diabetes of the young (MODY) (Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Wang et al. 2018. PubMed ID: 30293189; Goodrich et al. 2021. PubMed ID: 34108472. Supp Data 5). Of note, Goodrich et al. showed that this variant may have reduced penetrance. In addition, different missense substitutions at the same codon (p.Pro379Ala, p.Pro379Ser, Pro379His, Pro379Arg) have also been reported to be pathogenic for MODY (Dominguez-Lopez et al. 2005. PubMed ID: 15883474; Xu et al. 2005. PubMed ID: 15657605; Bellanne-Chantelot et al. 2008. PubMed ID: 18003757; Ekholm et al. 2013. PubMed ID: 23607861). Therefore, we classify the c.1135C>A (p.Pro379Thr) variant in this patient as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort. | Billings LK | Endocrinology, diabetes & metabolism | 2022 | PMID: 36208030 |
| Meta-analysis of HNF1A-MODY3 variants among human population. | Behl R | Journal of diabetes and metabolic disorders | 2022 | PMID: 35673428 |
| Unsupervised Clustering of Missense Variants in HNF1A Using Multidimensional Functional Data Aids Clinical Interpretation. | Althari S | American journal of human genetics | 2020 | PMID: 32910913 |
| New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population. | Ma Y | BMJ open diabetes research & care | 2020 | PMID: 32238361 |
| Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young. | Wang X | Acta diabetologica | 2019 | PMID: 30293189 |
| Determining the role of missense mutations in the POU domain of HNF1A that reduce the DNA-binding affinity: A computational approach. | P S | PloS one | 2017 | PMID: 28410371 |
| Clinical application of ACMG-AMP guidelines in HNF1A and GCK variants in a cohort of MODY families. | Santana LS | Clinical genetics | 2017 | PMID: 28170077 |
| Maturity-onset diabetes of the young (MODY) in Brazil: Establishment of a national registry and appraisal of available genetic and clinical data. | Giuffrida FMA | Diabetes research and clinical practice | 2017 | PMID: 28012402 |
| Successful maintenance on sulphonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. | Bacon S | Diabetic medicine : a journal of the British Diabetic Association | 2016 | PMID: 26479152 |
| MicroRNA-224 is Readily Detectable in Urine of Individuals with Diabetes Mellitus and is a Potential Indicator of Beta-Cell Demise. | Bacon S | Genes | 2015 | PMID: 26110317 |
| The clinical management of hyperglycemia in pregnancy complicated by maturity-onset diabetes of the young. | Bacon S | American journal of obstetrics and gynecology | 2015 | PMID: 25935773 |
| Circulating CD36 is reduced in HNF1A-MODY carriers. | Bacon S | PloS one | 2013 | PMID: 24069322 |
| Effects of hepatocyte nuclear factor-1A and -4A on pancreatic stone protein/regenerating protein and C-reactive protein gene expression: implications for maturity-onset diabetes of the young. | Kyithar MP | Journal of translational medicine | 2013 | PMID: 23803251 |
| Identification of circulating microRNAs in HNF1A-MODY carriers. | Bonner C | Diabetologia | 2013 | PMID: 23674172 |
| 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 | Human mutation | 2013 | PMID: 23348805 |
| Serum levels of pancreatic stone protein (PSP)/reg1A as an indicator of beta-cell apoptosis suggest an increased apoptosis rate in hepatocyte nuclear factor 1 alpha (HNF1A-MODY) carriers from the third decade of life onward. | Bacon S | BMC endocrine disorders | 2012 | PMID: 22808921 |
| Identification of HNF1A-MODY and HNF4A-MODY in Irish families: phenotypic characteristics and therapeutic implications. | Kyithar MP | Diabetes & metabolism | 2011 | PMID: 21683639 |
| The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. | Bellanné-Chantelot C | Diabetes | 2008 | PMID: 18003757 |
| Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. | Ellard S | Human mutation | 2006 | PMID: 16917892 |
| Mutations in MODY genes are not common cause of early-onset type 2 diabetes in Mexican families. | Domínguez-López A | JOP : Journal of the pancreas | 2005 | PMID: 15883474 |
| Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. | Xu JY | European journal of human genetics : EJHG | 2005 | PMID: 15657605 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5e9bf84c-2966-4860-b31d-dcfac7afc62e | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8505c6ba-0038-4b62-a7ce-49e36a42e940 | - | - | - | - |
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Text-mined citations for rs754729248 ...
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Record last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.