Submissions for variant NM_000545.8(HNF1A):c.620G>A (p.Gly207Asp)

dbSNP: rs1555211922

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002259986	SCV002540113	pathogenic	Monogenic diabetes	2022-06-10	reviewed by expert panel	curation	The c.620G>A variant in the HNF1 Homeobox A gene, HNF1A, causes an amino acid change of glycine to aspartic acid at codon 207 (p.(Gly207Asp)) of NM_000545.8. This variant was identified in an individual with a clinical history highly specific for HNF1A-MODY (MODY probability calculator result >50%, negative genetic testing for HNF4A, and response to low dose sulfonylurea) (PP4_Moderate). This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate). Furthermore, this variant segregated with diabetes, with 10 informative meioses, in one family with MODY (PP1_Strong). The glycine at the 207 codon position is located within a conserved region of the DNA binding domain (codons 107-174 and 201-280) of HNF1A, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.937, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.620G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.1, approved 9/30/2021): PP1_Strong, PM1_Supporting, PM2_Supporting, PS4_Moderate, PP4_Moderate, PP3.
Athena Diagnostics	RCV000516291	SCV000613624	uncertain significance	not specified	2017-05-09	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463451	SCV002604985	likely risk allele	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 rs1555211922 with MODY3.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002463451	SCV003922731	pathogenic	Maturity onset diabetes mellitus in young	2023-03-02	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.620G>A (p.Gly207Asp) results in a non-conservative amino acid change to a highly conserved residue located in the Homeobox domain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251266 control chromosomes. c.620G>A has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young (Ellard_2006, Frayling_2001, Kyithat_2011, Shepherd_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. An expert panel (ClinGen Monogenic Diabetes Variant Curation Expert Panel) (evaluation after 2014) cites the variant as pathogenic in ClinVar. Another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003328592	SCV004035580	likely pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16496320, 26110317, 22808921, 21683639, 20393147, 16917892, 24069322, 23803251, 12453420, 18003757, 35328643, 32395877, 31517624, 32910913, 35673428, 30229274, 23674172, 26479152)