rs28940300
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000551.4(VHL):c.574C>A(p.Pro192Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P192L) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.574C>A | p.Pro192Thr | missense_variant | 3/3 | ENST00000256474.3 | |
VHL | NM_198156.3 | c.451C>A | p.Pro151Thr | missense_variant | 2/2 | ||
VHL | NM_001354723.2 | c.*128C>A | 3_prime_UTR_variant | 3/3 | |||
VHL | NR_176335.1 | n.903C>A | non_coding_transcript_exon_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.574C>A | p.Pro192Thr | missense_variant | 3/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 23, 2021 | 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. This variant disrupts the p.Pro192 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19558618, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has been observed in individual(s) with bilateral pheochromocytoma (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with threonine at codon 192 of the VHL protein (p.Pro192Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. - |
Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | May 10, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.