ClinVar Miner

Submissions for variant NM_000458.4(HNF1B):c.140C>T (p.Pro47Leu)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000030521 SCV000053192 uncertain significance not specified 2019-01-17 criteria provided, single submitter clinical testing Variant summary: The variant, HNF1B (legacy name TCF2) c.140C>T (p.Pro47Leu) results in a non-conservative amino acid change located in the N terminal of Hepatocyte nuclear factor 1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.7e-05 in 245772 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.140C>T in individuals affected with Maturity Onset Diabetes of the Young 5 (Renal Cysts and Diabetes Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000730643 SCV000858394 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing
Institute of Human Genetics,Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000787252 SCV000926182 uncertain significance Renal cysts and diabetes syndrome 2019-07-06 criteria provided, single submitter literature only
Broad Institute Rare Disease Group,Broad Institute RCV000787252 SCV001423106 uncertain significance Renal cysts and diabetes syndrome 2020-01-22 no assertion criteria provided curation The p.Pro47Leu variant in HNF1B has been reported in at least 1 individual with Renal Cysts and Diabetes Syndrome in ClinVar (Variation ID: 36840), and has been identified in 0.02024% (7/34580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193922483). 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: 36840). 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.Pro47Leu variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).

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