Submissions for variant NM_000458.4(HNF1B):c.1006C>T (p.His336Tyr)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030518	SCV000053189	likely pathogenic	Renal cysts and diabetes syndrome	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000030518	SCV000926033	uncertain significance	Renal cysts and diabetes syndrome	2019-07-06	criteria provided, single submitter	literature only
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000030518	SCV001423107	uncertain significance	Renal cysts and diabetes syndrome	2020-01-22	criteria provided, single submitter	curation	The p.His336Tyr variant in HNF1B has been reported in at least 1 individual with Renal Cysts and Diabetes Syndrome in ClinVar (Variation ID: 377055), and has been identified in 0.02611% (9/34468) of Latino chromosomes and 0.0008848% (1/113020) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138986885). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36837). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.His336Tyr variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852605	SCV002183027	uncertain significance	not provided	2022-06-04	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 336 of the HNF1B protein (p.His336Tyr). This variant is present in population databases (rs138986885, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HNF1B-related conditions. ClinVar contains an entry for this variant (Variation ID: 36837). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV003398576	SCV004120679	uncertain significance	HNF1B-related disorder	2023-01-27	criteria provided, single submitter	clinical testing	The HNF1B c.1006C>T variant is predicted to result in the amino acid substitution p.His336Tyr. To our knowledge, this variant has not been reported in the literature in patients with HNF1B-related disorders. However, two different substitutions at the same codon (p.His336Arg, p.His336Asp) have been reported in patients with HNF1B-related disorders (p.His336Asp at Weber et al. 2006. PubMed ID: 16971658; p.His336Arg at Wang et al. 2017. PubMed ID: 28502589).This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-36091625-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.