ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.-12_2dup (p.Met1fs)

gnomAD frequency: 0.00001  dbSNP: rs886041253
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000270054 SCV000329563 likely benign not provided 2019-05-10 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge
Genetic Services Laboratory, University of Chicago RCV001820802 SCV002069321 uncertain significance not specified 2020-07-31 criteria provided, single submitter clinical testing DNA sequence analysis of the VHL gene demonstrated a 14 base pair duplication involving the 5′ untranslated region (5′UTR) and the translation start codon, c.-12_2dup. Though this duplication maintains the natural start codon sequence, ATG, its impact on the protein translation is not predictable. This sequence change does not appear to have been previously described in patients with VHL-related disorders and has been described in the gnomAD database with a frequency of 0.048% in the Latino sub-population (dbSNP rs1057522448). The functional significance of this sequence change is not known at present and its contribution to a disease phenotype cannot definitively be determined.
Ambry Genetics RCV002347985 SCV002647012 likely benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences RCV003909903 SCV004721482 uncertain significance VHL-related disorder 2023-11-15 criteria provided, single submitter clinical testing The VHL c.-12_2dup14 variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183519-G-GATCGCGGAGGGAAT/ ?dataset=gnomad_r2_1). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/279916/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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