rs754729248
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 7P and 4B. PP3PP4PP1_StrongBS1PM5_Supporting
This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA6831957/MONDO:0015967/017
Frequency
Consequence
NM_000545.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HNF1A | NM_000545.8 | c.1135C>A | p.Pro379Thr | missense_variant | 6/10 | ENST00000257555.11 | |
HNF1A | NM_001306179.2 | c.1135C>A | p.Pro379Thr | missense_variant | 6/10 | ||
HNF1A | NM_001406915.1 | c.1135C>A | p.Pro379Thr | missense_variant | 6/9 | ||
HNF1A | XM_024449168.2 | c.1135C>A | p.Pro379Thr | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HNF1A | ENST00000257555.11 | c.1135C>A | p.Pro379Thr | missense_variant | 6/10 | 1 | NM_000545.8 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250080Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135380
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461638Hom.: 0 Cov.: 36 AF XY: 0.0000165 AC XY: 12AN XY: 727136
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74332
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 18, 2023 | 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) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 22, 2023 | 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. - |
Maturity-onset diabetes of the young type 3 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | 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. - |
Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | 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). - |
Maturity onset diabetes mellitus in young Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 06, 2020 | 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. - |
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 14, 2023 | 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. - |
Type 1 diabetes mellitus 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at