3-10142082-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM5PP3_Moderate
The NM_000551.4(VHL):c.235C>T(p.Arg79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,605,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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VHL | NM_000551.4 | c.235C>T | p.Arg79Cys | missense_variant | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.235C>T | p.Arg79Cys | missense_variant | Exon 1 of 3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.235C>T | p.Arg79Cys | missense_variant | Exon 1 of 2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.305C>T | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000217 AC: 5AN: 230680Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 127772
GnomAD4 exome AF: 0.0000117 AC: 17AN: 1453488Hom.: 0 Cov.: 32 AF XY: 0.00000691 AC XY: 5AN XY: 723300
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Uncertain:3
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VHL-related disorder Uncertain:1
The VHL c.235C>T variant is predicted to result in the amino acid substitution p.Arg79Cys. This variant has been reported in the compound heterozygous state in an individual with congenital polycythemia (Bento et al. 2005. PubMed ID: 15642680). This variant is reported in 0.052% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-10183766-C-T). In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/161400/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Chuvash polycythemia Uncertain:1
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Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the VHL protein (p.Arg79Cys). This variant is present in population databases (rs200885420, gnomAD 0.04%). This missense change has been observed in individual(s) with congenital polycythemia (PMID: 15642680). ClinVar contains an entry for this variant (Variation ID: 161400). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. 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. -
not provided Uncertain:1
Identified in the compound heterozygous state in an individual with congenital polycythemia (Bento et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.448C>T; p.R150C. p.R120C; This variant is associated with the following publications: (PMID: 16210343, 25637381, 18538455, 17454194, 27651169, 23178531, 19295544, 20151405, 24729484, 23538339, 15642680) -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R79C variant (also known as c.235C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 235. The arginine at codon 79 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in the compound heterozygous state with another alteration in VHL in a patient with congenital polycythemia (Bento MC et al. Haematologica, 2005 Jan;90:128-9). This alteration has also been reported as a likely benign variant in an exome cohort, but clinical history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Polycythemia Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at