rs864622267
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP6
The NM_000551.4(VHL):c.307C>G(p.Pro103Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.307C>G | p.Pro103Ala | missense_variant | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.307C>G | p.Pro103Ala | missense_variant | Exon 1 of 3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.307C>G | p.Pro103Ala | missense_variant | Exon 1 of 2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.377C>G | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
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 expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 219823). This variant has been observed in individual(s) with pheocromocytoma (PMID: 21463266). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 103 of the VHL protein (p.Pro103Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant disrupts the p.Pro103 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 18928468, 23407919, 30877234), which suggests that this may be a clinically significant amino acid residue. 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. -
Hereditary cancer-predisposing syndrome Benign:1
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at