Submissions for variant NM_000545.8(HNF1A):c.1522G>A (p.Glu508Lys)

gnomAD frequency: 0.00003  dbSNP: rs483353044

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002468567	SCV002764626	benign	Monogenic diabetes	2022-12-01	reviewed by expert panel	curation	The c.1522G>A variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of glutamic acid to lysine at codon 508 (p.(Glu508Lys)) of transcript NM_000545.8. This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.002884, which is greater than the MDEP threshold for BA1 (greater than or equal to 0.0001) (BA1). This variant has been found in many unrelated individuals who do not have autoimmune or absolute/near-absolute insulin-deficient diabetes (PMID: 24915262); however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting. Functional studies demonstrated the p.Glu508Lys protein has transactivation activity between 40-80%, which is less severe than typical HNF1A-MODY-causing variants (below 40%) (PMID: 32910913, 27899486). In summary, this variant meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: BA1 (specification version 1.2, approved 6/5/21). However, this variant is an established risk allele for type 2 diabetes in individuals of Mexican ancestry (PMID: 24915262). These individuals do not respond to treatment with sulfonylureas, unlike individuals with HNF1A-MODY (PMID: 29844095).
Athena Diagnostics	RCV001640109	SCV000613602	likely benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517019	SCV001012093	likely benign	not provided	2023-10-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000988924	SCV001138845	uncertain significance	Maturity-onset diabetes of the young type 3	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390275	SCV002708184	likely benign	Maturity onset diabetes mellitus in young	2024-03-27	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	RCV001640109	SCV003800818	likely benign	not specified	2023-01-31	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1522G>A (p.Glu508Lys) results in a conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251600 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 19 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), strongly suggesting that the variant is benign. c.1522G>A has been reported in the literature as a non-significant risk factor in association with Type 2 diabetes (95% CI overlaps 1) (example, Estrada_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Maturity Onset Diabetes Of The Young 3. Four clinical diagnostic laboratories and an expert panel (ClinGen Monogenic Diabetes Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (B/LB, n=3 including the expert panel; VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign.
SNPedia	RCV000122743	SCV000165962	not provided	Type 2 diabetes mellitus		no assertion provided	not provided
PreventionGenetics, part of Exact Sciences	RCV003915222	SCV004736199	likely benign	HNF1A-related disorder	2021-05-27	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).