ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.1177G>A (p.Gly393Arg)

gnomAD frequency: 0.00001  dbSNP: rs757897768
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003234561 SCV003932657 benign Monogenic diabetes 2023-05-27 reviewed by expert panel curation The c.1177G>A in the HNF4A gene causes an amino acid change of glycine to arginine at codon 393 (p.Gly393Arg) of NM_15914.4. The nucleotide change c.1177G>C, which causes the same amino acid change, has been reported in a patient with monogenic diabetes; however, the c.1177G>C variant has not met the criteria to be classified as pathogenic for monogenic diabetes by the ClinGen MDEP. This variant was identified in three unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant is outside of the region defined as critical for the protein’s function by the ClinGen MDEP (codons 37-113, 180-220 and 300-350). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0000751, which is greater than the MDEP threshold for BS1 (greater than or equal to 0.000033) (BS1). This variant was identified in a normoglycemic individual >70 years old, and the expected penetrance for HNF4A-MODY is 95% by age 70 (internal lab contributor) (BS2). This variant has a REVEL score of 0.451, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on protein function. This variant was identified in individuals with diabetes; however, the MODY probability is unable to be calculated due to age of diagnosis over 35 and lack of clinical information (internal lab contributors). In summary, c.1177G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.0.0, approved 11/16/2022): BS1, BS2.
Genetic Services Laboratory, University of Chicago RCV000501691 SCV000595156 uncertain significance not specified 2016-07-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002506226 SCV002816457 uncertain significance Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 2022-04-14 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003148761 SCV003806249 uncertain risk allele Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in HNF4A are associated with poor insulin secretion in response to hyperglycemia. Associated with MODY1. Patients initially respond well to sulfonylureas but eventually become insulin dependent. However, more evidence is required to ascertain the role of this particular variant rs757897768 in MODY, yet.

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