Submissions for variant NM_000545.8(HNF1A):c.225C>T (p.Asp75=)

gnomAD frequency: 0.00009  dbSNP: rs202180554

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV001810424	SCV002060004	benign	Monogenic diabetes	2021-12-30	reviewed by expert panel	curation	The c.225C>T variant in the HNF1 homeobox A gene, HNF1A, is a synonymous (silent) variant at codon 75 (p.(Asp75=)) of NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.0007829, which is greater than or equal to the MDEP VCEP threshold for BA1 (≥0.0001) (BA1). Additionally, the c.225C>T variant is not predicted by SpliceAI to impact splicing (BP7). In summary, c.225C>T meets the criteria to be classified as benign for HNF1A-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.1, approved 6/4/2021): BA1, BP7.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000868182	SCV001009481	likely benign	not provided	2024-01-25	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002326822	SCV002601616	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 rs202180554 with MODY3.
Ambry Genetics	RCV002326822	SCV002733366	likely benign	Maturity onset diabetes mellitus in young	2018-02-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121188	SCV005204621	benign	not specified	2024-06-19	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.225C>T alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00017 in 235122 control chromosomes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in HNF1A causing Maturity Onset Diabetes Of The Young 3 phenotype (2.5e-05). To our knowledge, no occurrence of c.225C>T in individuals affected with Maturity Onset Diabetes Of The Young 3 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134505). Based on the evidence outlined above, the variant was classified as benign.
ITMI	RCV000121188	SCV000085357	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV003952601	SCV004775765	likely benign	HNF1A-related disorder	2023-12-14	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).