ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.124G>A (p.Gly42Arg)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003993724 SCV004812235 likely pathogenic Monogenic diabetes 2024-04-05 reviewed by expert panel curation The c.124G>A variant in the hepatocyte nuclear factor 4-alpha gene, HNF4A, causes an amino acid change of glycine to arginine at codon 42 (p.(Gly42Arg)) of NM_175914.5. This variant is located within the DNA binding domain (codons 37-113) of HNF4A, which is defined as crucial for the protein's function by the ClinGen MDEP (PM1_Supporting). This variant is also predicted to be deleterious by computational evidence, with a REVEL score of 0.948, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and zero copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in seven unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 26552609, internal lab contributors). However, the MODY probability is either unable to be calculated due to lack of clinical information or the calculated MODY probability is <50% (PMID:26552609, internal lab contributors). This variant segregated with diabetes, with three informative meioses in one family with MODY (PP1; PMID:26552609). In summary, c.124G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 10/11/2023): PS4, PP1, PP3, PM1_Supporting, PM2_Supporting.
Fulgent Genetics, Fulgent Genetics RCV005030371 SCV005656960 likely pathogenic Maturity-onset diabetes of the young type 1; Type 2 diabetes mellitus; Fanconi renotubular syndrome 4 with maturity-onset diabetes of the young 2024-05-10 criteria provided, single submitter clinical testing

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