Submissions for variant NM_000545.8(HNF1A):c.1548C>T (p.Gly516=)

dbSNP: rs886038346

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002250362	SCV002520651	uncertain significance	Monogenic diabetes	2022-05-02	reviewed by expert panel	curation	The c.1548C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 516 (p.(Gly516=)) of NM_000545.8. This variant has a minor allele frequency of 0.0000088 in the gnomAD v2.1.1 European non-Finnish population and no copies in another subpopulation, which is less than the ClinGen MDEP threshold for PM2_Supporting (less than or equal to 0.00002 and less than or equal to 1 copy in any other subpopulation) (PM2_Supporting). BP7 was not applied for this synonymous variant because SpliceAI predicts an impact on splicing, specifically a gain of a novel splice acceptor site (score = 0.47); however, PP3 was not applied because an acceptor loss was not predicted (score = 0.03). In summary, c.1548C>T meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PM2_Supporting.
PreventionGenetics, part of Exact Sciences	RCV000246843	SCV000305102	likely benign	not specified		criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463667	SCV002605160	likely benign	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 rs886038346 with MODY3.