Submissions for variant NM_000545.8(HNF1A):c.1136C>G (p.Pro379Arg)

gnomAD frequency: 0.00001  dbSNP: rs371717826

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003326011	SCV004032121	pathogenic	Monogenic diabetes	2023-08-14	reviewed by expert panel	curation	The c.1136C>G variant in the HNF1 homeobox A gene, HNF1A, causes an amino acid change of proline to arginine at codon 379 (p.(Pro379Arg)) of NM_000545.8. This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.961, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a MODY probability calculator result >50%, negative genetic testing for HNF4A, and antibody negative (PP4_Moderate; internal lab contributors). This variant was identified in 8 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID: 21170474, PMID: 15657605, internal lab contributors). This variant segregated with diabetes, with at least 4 informative meioses in 3 families with MODY (PP1_Strong; PMID: 15657605, internal lab contributors). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.1.0, approved 8/11/2023): PM2_Supporting, PP3, PP4_Moderate, PS4, PP1_Strong.
CeGaT Center for Human Genetics Tuebingen	RCV002211245	SCV002497641	likely pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	HNF1A: PM2, PM5, PS4:Moderate, PP3, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690266	SCV005185803	pathogenic	Maturity onset diabetes mellitus in young	2024-05-15	criteria provided, single submitter	clinical testing	Variant summary: HNF1A c.1136C>G (p.Pro379Arg) 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. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250114 control chromosomes (gnomAD). c.1136C>G has been reported in the literature in multiple individuals affected with Maturity Onset Diabetes Of The Young 3 (e.g. Xu_2005, Galan_2011, Pavic_2018, Colclough_2022). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant reduced transactivation in reporter assays (Galan_2011). The following publications have been ascertained in the context of this evaluation (PMID: 15657605, 21170474, 29666556, 34789499). ClinVar contains an entry for this variant (Variation ID: 1675516). Based on the evidence outlined above, the variant was classified as pathogenic.