rs864622646
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000551.4(VHL):c.345C>A(p.His115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H115P) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000551.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.345C>A | p.His115Gln | missense_variant | 2/3 | ENST00000256474.3 | |
VHL | NM_001354723.2 | c.*18-3269C>A | intron_variant | ||||
VHL | NM_198156.3 | c.341-3269C>A | intron_variant | ||||
VHL | NR_176335.1 | n.674C>A | non_coding_transcript_exon_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VHL | ENST00000256474.3 | c.345C>A | p.His115Gln | missense_variant | 2/3 | 1 | NM_000551.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 05, 2016 | Variant summary: This c.345C>A affects a non-conserved nucleotide, resulting in amino acid change from His to Gln. 2/3 in-silico tools predict this variant to be damaging. The residue p.His115 is reported to be critical for interaction with HIF, thus this missense change is unlikely to be tolerated. By a structural/functional assay, interaction energy of residue was ~1.5 kcal/mol weaker than that with histidine in the wild type (Domene_2012), thus proving that the variant leads to functional impairment. This variant was not found in approximately 121600 control chromosomes, including the broad and large populations from ExAC. In literature, the p.His115Gln has been reported as a pathogenic variant found in >6 independent VHL patients/families, including somatic occurrences. At least one database calls this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 19, 2019 | This variant has been reported to affect VHL protein function (PMID:28775317). This missense change has been observed in individuals with Von Hippel-Lindau syndrome (VHL) or clinical features of VHL (PMID: 19949673, 9829912, 7728151, 9681856, 29749453). ClinVar contains an entry for this variant (Variation ID: 496057). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 115 of the VHL protein (p.His115Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant disrupts the p.His115 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 17024664, 8707293, 22357542), which suggests that this may be a clinically significant amino acid residue. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at