ClinVar Miner

Submissions for variant NM_000458.4(HNF1B):c.662A>T (p.Asp221Val)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000787167 SCV000926097 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 RCV001248889 SCV001422569 benign Maturity onset diabetes mellitus in young 2020-01-22 criteria provided, single submitter curation The p.Asp221Val variant in HNF1B has not been previously reported in individuals with MODY but has been identified in 0.03% (6/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs755263300). This variant has been seen in the general population at a frequency high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, this variant meets criteria to be classified as benign for MODY in an autosomal dominant manner based on the frequency in the general population. ACMG/AMP Criteria applied: BA1 (Richards 2015).
Invitae RCV001869184 SCV002306108 uncertain significance not provided 2021-06-21 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with clinical features of HNF1B-related conditions (PMID: 22051731). ClinVar contains an entry for this variant (Variation ID: 635666). This variant is present in population databases (rs755263300, ExAC 0.01%). This sequence change replaces aspartic acid with valine at codon 221 of the HNF1B protein (p.Asp221Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine.

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