ClinVar Miner

Submissions for variant NM_000551.4(VHL):c.429C>T (p.Asp143=)

gnomAD frequency: 0.00001  dbSNP: rs773556807
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000470382 SCV000563217 likely pathogenic Chuvash polycythemia; Von Hippel-Lindau syndrome 2024-09-18 criteria provided, single submitter clinical testing This sequence change affects codon 143 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein. This variant is present in population databases (rs773556807, gnomAD 0.006%). This variant has been observed in individuals with autosomal recessive erythrocytosis and/or endometrial cancer (PMID: 29891534, 36744932). This variant is also known as D143D. ClinVar contains an entry for this variant (Variation ID: 416990). Studies have shown that this variant alters VHL gene expression (PMID: 29891534; internal data). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000564320 SCV000664611 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-17 criteria provided, single submitter clinical testing The c.429C>T variant (also known as p.D143D), located in coding exon 2 of the VHL gene, results from a C to T substitution at nucleotide position 429. This nucleotide substitution does not change the aspartic acid at codon 143. This variant has been identified in the homozygous state and in trans with a VHL variant in individuals diagnosed with erythrocytosis (Lenglet M et al. Blood, 2018 Aug;132:469-483). This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing; however, RNA studies have detected abnormal splicing associated with this variant (Lenglet M et al. Blood, 2018 Aug;132:469-483, Ambry internal data). Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx RCV000613763 SCV000714522 likely benign not specified 2018-01-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen RCV002056727 SCV002496780 likely benign not provided 2022-03-01 criteria provided, single submitter clinical testing VHL: BP4, BP7
All of Us Research Program, National Institutes of Health RCV004002229 SCV004841651 uncertain significance Von Hippel-Lindau syndrome 2023-06-26 criteria provided, single submitter clinical testing This variant causes a C>T nucleotide change in exon 2 of the VHL gene. An RNA study has reported that this variant results in the incomplete out-of-frame skipping of exon 2 and a corresponding reduction in VHL gene expression in RNA from two homozygous carriers and a compound heterozygous carrier with an intron 2 variant (PMID: 29891534). To our knowledge, this variant has not been reported in individuals affected with VHL-associated hereditary cancer in the literature. This variant has been identified in 2/251492 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics RCV005027539 SCV005658803 uncertain significance Chuvash polycythemia; Pheochromocytoma; Von Hippel-Lindau syndrome; Nonpapillary renal cell carcinoma 2024-03-19 criteria provided, single submitter clinical testing

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