ClinVar Miner

Submissions for variant NM_000545.8(HNF1A):c.340C>T (p.Arg114Cys)

gnomAD frequency: 0.00001  dbSNP: rs774996577
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV005401814 SCV006059958 uncertain significance Monogenic diabetes 2025-04-23 reviewed by expert panel curation The c.340C>T variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of arginine to cysteine at codon 114 (p.(Arg114Cys)) of NM_000545.8. This variant is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.952, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Functional studies demonstrated the p.Arg114Cys protein has DNA binding above 75% of wild type, normal localization, and transactivation above 75% of wildtype, indicating that this variant does not impact protein function (BS3_Supporting; PMID: 26853433). The Grpmax filtering allele frequency of the c.340C>T variant in gnomAD v2.1.1 is 0.00002596, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant was identified in four 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:26853433, 19336507, ClinVar, internal lab contributors). In summary, c.340C>T meets the criteria to be classified as 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): PM1_Supporting, PP3, BS3_Supporting.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV001248949 SCV001422728 uncertain significance Maturity-onset diabetes of the young type 3 2020-01-22 criteria provided, single submitter curation The p.Arg114Cys variant in HNF1A has not been previously reported in individuals with maturity-onset diabetes of the young and has been identified in 0.01% (3/30610) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs774996577). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg114Cys variant is uncertain. ACMG/AMP Criteria applied: BS1, PP3 (Richards 2015).
Molecular Genetics, Madras Diabetes Research Foundation RCV002051926 SCV002318386 uncertain significance Maturity onset diabetes mellitus in young criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002051926 SCV002758781 likely risk allele Maturity onset diabetes mellitus in young criteria provided, single submitter research Mutations in HNF1A gene can predispose to MODY3. It is associated with both micro and macrovascular complications of diabetes, especially cardiovascular complications. Associated with glucosuria. May respond well to sulfonylureas. However, more evidence is required to confer the association of this particular variant rs774996577 with MODY3.
GeneDx RCV004797916 SCV005419917 uncertain significance not provided 2024-05-23 criteria provided, single submitter clinical testing Reported in an individual with suspected MODY in published literature (PMID: 19336507); detailed clinical and segregation information not provided; Published functional studies demonstrate impaired DNA binding but do not significantly impact transcription, expression, or nuclear localization (PMID: 26853433, 32910913); further studies are necessary to elucidate the role of the variant; Located in the critical DNA binding domain (PMID: 12453420, 18003757); 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: 26853433, 12453420, 18003757, 32910913, 23348805, 19336507)
Fulgent Genetics, Fulgent Genetics RCV005005125 SCV005632351 uncertain significance Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma 2024-06-03 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV001248949 SCV006070574 likely pathogenic Maturity-onset diabetes of the young type 3 2024-02-01 criteria provided, single submitter clinical testing Missense 0.001% Polyphen: possibly damaging SIFT: damaging MutationTaster: disease causing CADD Phred: damaging SpliceAI: NA GERP++ PhyloP Uncertain Significance/Likely risk allele Yes Radha V, et al., 2019; Balamurugan K, et al., 2016

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