Submissions for variant NM_000545.8(HNF1A):c.1015G>A (p.Gly339Ser)

gnomAD frequency: 0.00004  dbSNP: rs766790596

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000369590	SCV000376715	likely benign	Maturity-onset diabetes of the young type 3	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000866953	SCV001008126	likely benign	not provided	2023-08-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001642957	SCV001146093	likely benign	not specified	2020-10-05	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002319476	SCV002604898	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 rs766790596 with MODY3.
Fulgent Genetics, Fulgent Genetics	RCV002494960	SCV002805717	likely benign	Diabetes mellitus type 1; Type 1 diabetes mellitus 20; Maturity-onset diabetes of the young type 3; Type 2 diabetes mellitus; Hepatic adenomas, familial; Nonpapillary renal cell carcinoma	2021-11-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001642957	SCV004122288	likely benign	not specified	2023-10-28	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1015G>A (p.Gly339Ser) results in a non-conservative amino acid change located in the Hepatocyte nuclear factor 1, beta isoform, C-terminal domain (IPR006897) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251398 control chromosomes, predominantly in the Latino and South Asian subpopulations at a frequencies of 0.00087 and 0.00046, respectively, in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 35-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 a benign polymorphism found primarily in populations of Latino origin. c.1015G>A has been reported in the literature in unaffected control individuals, individuals affected with Maturity Onset Diabetes Of The Young, or Type 2 or other unspecified diabetes, predominantly of South Asian and Latino descent with frequent benign variant classifications (e.g. Sampathkumar_2022, Juszczak_2019, Lakshmanan_2021, Althari_2020). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (e.g. Althari_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32910913, 30455330, 32418360, 34741762). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.