ClinVar Miner

Submissions for variant NM_175914.5(HNF4A):c.408G>A (p.Ala136=)

gnomAD frequency: 0.00009  dbSNP: rs374298096
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003126918 SCV003802725 likely benign Monogenic diabetes 2023-01-12 reviewed by expert panel curation The c.408G>A variant in the hepatocyte nuclear factor 4 alpha gene, HNF4A, is a synonymous (silent) variant at codon 136 (p.(Ala136=)) of NM_175914.5. This variant is not predicted by SpliceAI to impact splicing (SpliceAI scores less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of -1.087, which is below the MDEP cutoff of 2.0) (BP4, BP7). The Popmax frequency of the c.408G>A variant in gnomAD v2.1.1 is 0.00002619, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. In summary, c.408G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.0, approved 11/16/22): BP4, BP7.
Athena Diagnostics RCV000711957 SCV000842368 benign not provided 2017-12-30 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV003148848 SCV003804630 benign 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 rs374298096 in MODY, yet.
Labcorp Genetics (formerly Invitae), Labcorp RCV000711957 SCV004276483 benign not provided 2023-06-15 criteria provided, single submitter clinical testing
Breakthrough Genomics, Breakthrough Genomics RCV000711957 SCV005311835 benign not provided criteria provided, single submitter not provided

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