Submissions for variant NM_000458.4(HNF1B):c.949G>T (p.Ala317Ser)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030535	SCV000053206	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	RCV000030535	SCV000926043	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	RCV000030535	SCV001423105	uncertain significance	Renal cysts and diabetes syndrome	2020-01-22	criteria provided, single submitter	curation	The p.Ala317Ser variant in HNF1B has been reported in at least 1 individual with Renal Cysts and Diabetes Syndrome in ClinVar (Variation ID: 36854), and has been identified in 0.008674% (3/34588) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922492). 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. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36854). In summary, the clinical significance of the p.Ala317Ser variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852607	SCV002301963	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt HNF1B protein function. ClinVar contains an entry for this variant (Variation ID: 36854). This variant has not been reported in the literature in individuals affected with HNF1B-related conditions. This variant is present in population databases (rs193922492, gnomAD 0.009%). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 317 of the HNF1B protein (p.Ala317Ser).