The HNF1A NM_000545.8:c.608G>A (NP_000536.6:p.(Arg203His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV109409878, n = 1 time). Experimental evidence: Transfected-cell immunofluorescence showed relatively preserved p.Arg203His localization, with 83% nucleus-only cells versus 99% for wild type. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be Pathogenic by the VCEP (ClinGen Monogenic Diabetes Variant Curation Expert Panel; ClinVar ID 129235).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.HNF1A encodes a transcription factor that helps control the activity of genes important for liver function and pancreatic islet cells. Inherited loss of HNF1A function causes maturity-onset diabetes of the young type 3 (MODY3), and changes in the gene can lead to hepatic adenomas. HNF1A acts as a tumor suppressor, with its inactivation commonly associated with hepatocellular adenomas and rarely found in hepatocellular carcinoma.
The recorded framework is ClinGen HNF1A VCEP v3.1. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at Moderate: p.Arg203His changes Arg203, explicitly listed by the VCEP as a direct DNA-binding residue.
Met: REVEL score 0.958 exceeds the VCEP PP3 threshold of ≥0.70 for this missense variant.
Not applicable: the HNF1A VCEP explicitly prohibits PP5 use, regardless of available pathogenic assertions.
Met at supporting strength: transfected-cell immunofluorescence showed relatively preserved p.Arg203His localization, with 83% nucleus-only cells versus 99% for wild type.
VUS: PM1 (moderate), PP3 (supporting), PP5 (supporting), and BS3 (supporting) do not satisfy a VCEP pathogenic or benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 2 / 1,614,156 alleles. Recorded AF 1.23904e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15915e-05; MAF= 0.00616%, 1/16236 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.958. Refer to the recorded PP3/BP4 rationale for interpretation.
6 Pathogenic · 2 Likely pathogenic. ClinVar API review status: reviewed by expert panel.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HNF1A, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HNF1A are associated with Maturity Onset Diabetes
This variant has previously been reported in somatic cancers (COSMIC; COSV109409878, n = 1 times).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under ClinGen HNF1A VCEP v3.1, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 2 not met · 13 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PM1 is met at Moderate because the VCEP explicitly lists Arg203 as a direct DNA-binding residue.
PS1 and PM5 remain not_assessed because qualifying alternate-variant classifications were not verified and the comparator retrieval reported HTTP 429.
PP2 and BP1 are not applicable under the HNF1A VCEP specification.
The available evidence documents R203H in an affected proband and inconclusive family screening, but does not establish confirmed de novo status, countable cosegregation meioses, or the VCEP's BS4 MPC requirement.
PM6 is explicitly Not Applicable under the HNF1A VCEP CSPEC entry.
Under the ClinGen Monogenic Diabetes HNF1A VCEP v3.1, PP5 and BP6 are not applicable; PP4 and BP5 lack required case-level inputs; PS4 cannot be used because the required PM2_Supporting prerequisite is not evaluable from the available Grpmax FAF data.
PP3 is met at Supporting strength from the VCEP-named REVEL missense path; BP4 is not met because the same REVEL score is above the benign cutoff; BP7 is not applicable because the variant is missense rather than synonymous.
The SpliceAI result was not double-counted across criteria and was not used for the missense-specific PP3 or BP4 decisions.
No literature source was needed to adjudicate these predictor-defined criteria.
No criteria match.
The HNF1A VCEP's PM1 Moderate rule explicitly lists Arg203 among residues that directly bind DNA. The case variant is p.Arg203His, so its altered residue is exactly one of the VCEP-specified DNA-binding residues. The VCEP domain_tables entry for HNF1A is empty; therefore no additional authoritative domain-table list changes this direct residue-specific match. The structural study independently describes Arg203 as making base-specific and DNA-backbone hydrogen bonds and reports that R203C/H disrupt these interactions.
This criterion can be used for variants in residues that directly bind DNA: Gln130, Arg131, Glu132, His143, Leu144, Ser145, Gln146, His147, Leu148, Asn149, Lys155, Thr156, Gln157, Lys158, Arg203, Phe204, Lys205, Trp206, Arg263, Val264, Tyr265, Asn270, Arg271, Arg272, Lys273
The VCEP applies PP3 at Supporting strength to a missense variant when REVEL is ≥0.70; its separate SpliceAI path is limited to non-canonical splicing and synonymous variants. This variant is a missense substitution, NM_000545.8:c.608G>A (p.Arg203His), and the governing predictor for this situation is REVEL. The REVEL score is 0.958, which is above the VCEP threshold of 0.70, so PP3 is met. The SpliceAI max delta score of 0.105 is not additionally counted because SpliceAI is not the named PP3 path for this missense situation.
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2[<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
Expert panel ClinGen Monogenic Diabetes Variant Curation Expert Panel classified as Pathogenic.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BS3 is met at supporting strength. The VCEP permits supporting BS3 from western blotting or indirect immunofluorescence studies of protein expression or localization and requires that the study be performed on a transfected variant. PMID:16274290 used transiently transfected HNF-1alpha constructs in HeLa cells and found p.Arg203His had relatively preserved, more normal localization: 83% nucleus-only and 17% nuclear-plus-cytoplasmic staining among 100 cells, versus 99% nucleus-only for wild type. This variant-specific transfected-cell result supports no damaging effect on localization, although it does not establish normal transactivation or DNA binding.
To use BS3, functional study must have been performed on a transfected variant. If a study was performed on a cell line generated from a patient sample (and therefore contains the variant plus wild-type allele and other variants in the patient’s genome) it cannot count as BS3. ... BS3 should be applied at the supporting level for the following approved functional studies and cutoffs: ... 3. Western blotting and indirect immunoflorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between different experimental protocols. Altered protein expression can be indirectly captured through the read-out from a transactivation assay and reduced protein expression can provide an explanation for reduced transactivation.
PS3 is not met. The available variant-specific functional study was an indirect immunofluorescence localization assay in transfected HeLa cells, not a damaging transactivation or DNA-binding assay. For p.Arg203His, 83% of 100 cells showed nucleus-only localization and 17% showed both nuclear and cytoplasmic staining, compared with 99% nucleus-only localization for wild-type HNF-1alpha; the authors described the variant as having a more normal subcellular distribution. These results do not provide evidence of decreased function under the VCEP's PS3 rule.
PS3 should be applied at the supporting level for the following approved functional studies and cutoffs except as noted in the PS3\_Moderate specification: ... 3. Western blotting and indirect immunofluorescence for protein expression and localization - Determining appropriate thresholds for protein expression is more difficult due to variability in results between experimental protocols. Altered protein expression can be indirectly captured through the read-out frame from transactivation assay, and reduced protein expression can provide an explanation for reduced transactivation. When exploring protein mis-localization, we recommend that the c.589\_615del (p.Lys197\_Lys205del) variant is included as a positive control for impaired nuclear localization (cytosolic retention).
The VCEP applies BP4 at Supporting strength to a missense variant using REVEL ≤0.15; its separate SpliceAI path is limited to non-canonical splicing and synonymous variants. This variant is missense, so REVEL is the governing predictor for this situation. The REVEL score is 0.958, not ≤0.15, and therefore does not support no predicted impact. The SpliceAI max delta score of 0.105 is not used to rescue BP4 because SpliceAI is not the named BP4 path for this missense situation.
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 [<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
The HNF1A VCEP permits PS1 at Strong only for the same amino-acid change when a previously established variant is pathogenic by ClinGen MDEP specifications. The available evidence confirms the case variant as p.Arg203His, but does not verify a distinct previously established pathogenic variant producing the same amino-acid change. The targeted comparator collection found no same-residue candidates but reported an HTTP 429 failure, so the absence of a qualifying comparator is not sufficiently established for a definitive not_met call.
Applicable for a same amino acid change if the previously established variant is classified as pathogenic by ClinGen MDEP specifications.
The VCEP directs PS2 assessment through its point-based de novo system, but the available variant-specific evidence does not establish a de novo event. PMID:11315828 reports that the HK54 proband carried R203H and that none of the diabetic or nondiabetic relatives who presented for screening carried the mutation; it does not document confirmed parental relationships or parental testing establishing de novo status. PMID:10588527 identifies R203H in family HK54 but provides no variant-specific parental testing. The governing PS2_DeNovo_Points_Table.pdf was searched for c.608G>A, p.Arg203His, and p.R203H, with no variant-specific entry found, so no pre-assigned de novo code can be applied.
Use SVI recommended point-based system with specifications for “Phenotype Consistency” described in PP4 specifications.
The HNF1A VCEP requires the variant to meet PM2_Supporting before PS4 can be used, but the available gnomAD records provide allele counts/frequencies without the required gnomAD Grpmax FAF, so that prerequisite cannot be evaluated under the VCEP rule. The literature documents R203H in two apparently unrelated affected-family reports: HK54 in PMID:10588527/PMID:11315828 is one occurrence, and Family #238 in PMID:15657605 is a second; PMID:12453420 discusses R203H but does not provide an independent occurrence. PMID:15657605 reports absence from 100 nondiabetic controls, but no complete affected/control case-control counts permitting an OR and 95% CI are provided. Thus PS4 cannot be applied despite the reported affected occurrences.
Variant should meet PM2\_Supporting in order to use PS4 at any level (careful review of gnomAD QC data may be necessary to assess whether variant is real or an artifact, especially if variant is in a polyC region). ... Seven or more unrelated occurrences = Strong. ... 4-6 unrelated occurrences = Moderate.
The HNF1A VCEP requires gnomAD Grpmax FAF <= 1:333,000 (<= 0.000003 or 0.0003%) for PM2 Supporting. The governing text does not specify a non-cancer or exome-only source, so the applicable default is the all-comers gnomAD record; its Grpmax FAF is null in both v2.1 and v4.1. The reported total AF values cannot substitute for Grpmax FAF, so PM2 cannot be assessed.
gnomAD Grpmax FAF <= 1:333,000 (<= 0.000003 or 0.0003%)
The VCEP provides PM5 rules for pathogenic or likely pathogenic alternate amino-acid changes at the same residue, including a Grantham-distance comparison for the Moderate path. The literature extraction identifies R203C and R203G as alternate changes at residue 203, but it does not establish either as pathogenic or likely pathogenic by the governing VCEP. The targeted PM5 candidate collection found no qualifying same-residue candidates and reported an HTTP 429 failure; therefore PM5 cannot be definitively applied or excluded from the available evidence.
Applicable once two amino acid changes have been classified as pathogenic at the same amino acid residue ... The novel amino acid change must have a Grantham distance greater than or equal to the previously classified pathogenic variant. ... Apply if the previously classified amino acid change is likely pathogenic (rather than pathogenic), or if the previously classified variant is pathogenic but has a greater Grantham distance.
The VCEP requires Jarvik and Browning meiosis thresholds: for a single family, supporting evidence requires at least 3 meioses, moderate at least 4 meioses, and strong at least 5 meioses; for more than one family, the corresponding thresholds are 2, 3, and 4 meioses. PMID:11315828 states that segregation for HK54 was inconclusive because none of the diabetic or nondiabetic relatives who presented for screening carried R203H, but it does not provide a count of informative meioses or sufficient family genotypes for threshold calculation. Therefore PP1 cannot be assessed.
Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918) ... Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918) ... Use thresholds suggested by Jarvik and Browning[<sup>7</sup>](#pmid_27236918)
The HNF1A VCEP requires an MPC result of at least 50% and negative HNF4A testing for PP4 Supporting; Moderate additionally requires at least one specified HNF1A-MODY feature. The case evidence does not provide an MPC result, HNF4A testing result, or sufficient patient-level phenotype data to evaluate these requirements. PP4 is therefore not assessed rather than inferred from the variant's published disease association.
MODY Probability Calculator (MPC) result ≥50% chance of testing positive https://www.diabetesgenes.org/mody-probability-calculator/) AND negative HNF4A testing ... MODY Probability Calculator (MPC) result ≥50% chance of testing positive [https://www.diabetesgenes.org/mody-probability-calculator/](https://www.diabetesgenes.org/mody-probability-calculator/)) AND negative HNF4A testing AND presence of at least one additional feature characteristic of HNF1A-MODY: * Antibody negative and/or persistent C-peptide after five years post-T1DM diagnosis * Response to low-dose sulfonyurea (SU) (extreme response- hypoglycemia) * Low hsCRP in patient with clinical diagnosis of T2DM * Biochemical/Molecular phenotypic evidence from patient cell lines * Hepatocellular adenomas
The HNF1A VCEP requires gnomAD Grpmax FAF >= 1:10,000 (>= 0.01% or 0.0001). The available gnomAD v2.1 and v4.1 records report population allele frequencies, but Grpmax FAF is null in both records; therefore the VCEP threshold cannot be evaluated without substituting a different metric.
gnomAD Grpmax FAF >= 1:10,000 (>= 0.01% or 0.0001)
The HNF1A VCEP requires gnomAD Grpmax FAF >= 1:30,000 (>=0.0033% or 0.000033). The available gnomAD v2.1 and v4.1 records report population allele frequencies, but Grpmax FAF is null in both records; therefore the VCEP threshold cannot be evaluated without substituting a different metric.
gnomAD Grpmax FAF >= 1:30,000 (>=0.0033% or 0.000033)
The HNF1A VCEP applies BS2 to normoglycemic individuals age 70 or older who carry the variant. gnomAD reports zero homozygotes, but it does not provide evidence here that any identified carrier was normoglycemic and age 70 or older; the criterion therefore cannot be evaluated.
Apply to normoglycemic individuals age 70 or older (i.e., genotype positive, phenotype negative)
The VCEP limits BS4 to family members without the variant who have an MPC score greater than 50%, meaning genotype-negative and phenotype-positive relatives. PMID:11315828 reports that screened diabetic and nondiabetic family members did not carry R203H, but it does not provide MPC scores or establish the required genotype-negative, phenotype-positive relatives with MPC >50%. The evidence therefore cannot satisfy the VCEP BS4 rule.
Applicable to family members without variant who have MPC score >50% (i.e., genotype negative, phenotype positive).
The HNF1A VCEP permits BP2 when the variant is in cis or trans with a likely pathogenic variant. The available variant-specific literature reports HNF1A p.Arg203His in affected probands and provides segregation observations, but does not identify a second likely pathogenic variant or establish cis/trans phase. No qualifying BP2 observation is therefore available.
Also applicable when in cis or trans with a likely pathogenic variant.
The HNF1A VCEP BP5 rule requires a variant in another monogenic diabetes gene to be classified as pathogenic or likely pathogenic. The available evidence does not identify a co-occurring variant in another monogenic diabetes gene in this case, so BP5 cannot be evaluated and is not assessed.
A variant in other monogenic diabetes gene is P/LP.
The governing HNF1A VCEP PVS1 rule applies PVS1 to nonsense or frameshift variants. NM_000545.8:c.608G>A (NP_000536.6:p.(Arg203His), p.(R203H)) is a missense variant in exon 3, not a truncating or qualifying splice variant, so the PVS1 pathway does not apply and no NMD, exon-importance, or protein-length-loss calculation is relevant. The governing PVS1 decision-tree file was searched for c.608G>A, p.Arg203His, and p.R203H; no matching entry was found.
Apply PVS1 to nonsense or frameshift variants occurring 5' of c.1768.
The HNF1A VCEP CSPEC explicitly marks PM3 as not applicable. Therefore, no recessive inheritance, affected-proband, or phase evidence is evaluated under PM3 for this interpretation.
Not Applicable
The HNF1A VCEP PM4 specification is limited to deletions or insertions of more than one amino acid in a non-repeat region, or single-amino-acid deletions/insertions. NM_000545.8:c.608G>A produces the missense substitution p.Arg203His and is neither a deletion nor an insertion, so PM4 is not applicable.
For deletions/insertions of more than one amino acid in a non-repeat region, use as moderate level of evidence. ... For single amino acid deletions/insertions, use as supporting level of evidence
The HNF1A VCEP CSPEC entry explicitly marks PM6 as Not Applicable. The governing PS2_DeNovo_Points_Table.pdf was nevertheless searched for c.608G>A, p.Arg203His, and p.R203H; no variant-specific pre-assigned code was found.
Not Applicable
The HNF1A VCEP marks PP2 as Not Applicable. No PP2 evidence is adjudicated.
Not Applicable
The HNF1A VCEP marks BP1 as Not Applicable. No BP1 evidence is adjudicated.
Not Applicable
The HNF1A VCEP explicitly designates BP3 as not applicable. Therefore repeat-region context cannot activate BP3 under this governing framework, regardless of the variant's local sequence context.
Not Applicable
BP6 is explicitly not applicable under the governing ClinGen Monogenic Diabetes HNF1A VCEP specification. Benign assertions from published sources or ClinVar therefore cannot be used as BP6 in this interpretation.
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
The VCEP's BP7 applicability describes a synonymous variant evaluated for absent splice impact and low conservation. This variant is missense, NM_000545.8:c.608G>A (p.Arg203His), so it lies outside BP7's governing scope. BP7 is therefore not applicable; the available SpliceAI score is not evaluated for this criterion.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved... Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \< 2.0.
Every interpreted variant in HNF1A, mapped onto the exon structure of NM_000545.8. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| African/African American1 / 75,042 | 1.3e-05 |
| European (non-Finnish)1 / 1,180,016 | 8.5e-07 |
| African/African American1 / 16,236 | 6.2e-05 |
| European (non-Finnish)1 / 113,676 | 8.8e-06 |
This variant is present in gnomAD v4.1 (AF= 1.23904e-06; MAF= 0.00012%, 2/1614156 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33259e-05; MAF= 0.00133%, 1/75042 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15915e-05; MAF= 0.00616%, 1/16236 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The VCEP applies PP3 at Supporting strength to a missense variant when REVEL is ≥0.70; its separate SpliceAI path is limited to non-canonical splicing and synonymous variants. This variant is a missense substitution, NM_000545.8:c.608G>A (p.Arg203His), and the governing predictor for this situation is REVEL. The REVEL score is 0.958, which is above the VCEP threshold of 0.70, so PP3 is met. The SpliceAI max delta score of 0.105 is not additionally counted because SpliceAI is not the named PP3 path for this missense situation.
Use REVEL score of ≥0.70 as supportive evidence of pathogenicity. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply PP3 when the predicted change is above 0.2[<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
The VCEP applies BP4 at Supporting strength to a missense variant using REVEL ≤0.15; its separate SpliceAI path is limited to non-canonical splicing and synonymous variants. This variant is missense, so REVEL is the governing predictor for this situation. The REVEL score is 0.958, not ≤0.15, and therefore does not support no predicted impact. The SpliceAI max delta score of 0.105 is not used to rescue BP4 because SpliceAI is not the named BP4 path for this missense situation.
Use a REVEL score of ≤0.15 as supportive evidence of no predicted impact on the gene or gene product. We also support using SpliceAI to assess the predicted impact of non-canonical splicing variants and synonymous variants: apply BP4 when the predicted change is below 0.2 [<sup>8</sup>](#pmid_32123317),[<sup>9</sup>](#pmid_30661751).
The VCEP's BP7 applicability describes a synonymous variant evaluated for absent splice impact and low conservation. This variant is missense, NM_000545.8:c.608G>A (p.Arg203His), so it lies outside BP7's governing scope. BP7 is therefore not applicable; the available SpliceAI score is not evaluated for this criterion.
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved... Apply BP7 when the predicted change from SpliceAI is below 0.2 AND phyloP100 way \< 2.0.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.958. BayesDel score = 0.56578.
8 paper records listed. 2 cited in the classification.
Residues within the HNF-1α sequence KKGRRNRFK (197–205) undoubtedly serve this purpose. MODY3 mutations R200Q, R200W, R203C, and R203H within the putative NLS are thus predicted to hinder nuclear translocation.
Location Results and Discussion, 'DNA Recognition by HNF-1alpha' and 'Rationalizing Diabetes Mutations'; Table 2
Context X-ray crystal structure of human HNF-1alpha residues 83-279 bound to consensus promoter DNA, with transcriptional reporter assays and structure-based categorization of MODY3 substitutions; no R203H-specific assay result is provided.
Whereas proteins containing the patient mutations R203H and R205Q (located in the C-terminal part of region B) showed a more normal subcellular distribution.
Location Results, 'Subcellular localization of HNF-1alpha mutants,' region B; Table 1
Context Transient transfection of epitope-tagged wild-type or mutant HNF-1alpha constructs into HeLa cells, followed by immunofluorescence assessment of nuclear versus cytoplasmic localization; R203H: 83% nucleus only, 17% nucleus and cytoplasm, n=100.
HK54 HNF-1alpha R203H
Clinical genotype table, family HK54
Segregation was inconclusive in the other six families. For the families of three patients (HK54 with HNF-1a R203H, YDM83 with mt3243, and CX216 with amylin S20G mutations), the probands carried the gene mutations, but none of the diabetic or nondiabetic family members who presented for screening carried the mutations.
Table 1; Results, "Family cosegregation study of gene mutations" paragraph
#238 3 203 CGT-CAT Arg-His R203H The missense mutations R203H, Q243E, A311D and P379R are predicted to change the protein structure, according to the Chou-Fasman plot.19 None of the mutations was detected in the 100 nondiabetic controls and, based on the family cosegregation studies, reported functional studies or anticipated changes in amino acids, all mutations are likely to have functional significance.
Results, Table 1; Discussion, paragraph 2
Mutations g.2707C>T and g.2707C>G are located in the same locus but generate different amino acidic changes.
Table 1; Discussion, paragraph beginning 'Mutations g.2707C>T and g.2707C>G...'
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.23904e-06; MAF= 0.00012%, 2/1614156 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33259e-05; MAF= 0.00133%, 1/75042 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 7.95805e-06; MAF= 0.00080%, 2/251318 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.15915e-05; MAF= 0.00616%, 1/16236 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen Monogenic Diabetes Variant Curation Expert Panel (expert panel). (ClinVarID = 129235)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.958. BayesDel score = 0.56578.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. HNF1A, a transcription factor, is altered by mutation in various cancer types. Germline mutations of HNF1A are associated with Maturity Onset Diabetes
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109409878, n = 1 times).
This variant does not lie in a statistically significant hotspot.