3-10141850-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PVS1_StrongPS1_ModerateBP6
The NM_000551.4(VHL):c.3G>T(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,535,406 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000551.4 start_lost
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
VHL | NM_000551.4 | c.3G>T | p.Met1? | start_lost | Exon 1 of 3 | ENST00000256474.3 | NP_000542.1 | |
VHL | NM_001354723.2 | c.3G>T | p.Met1? | start_lost | Exon 1 of 3 | NP_001341652.1 | ||
VHL | NM_198156.3 | c.3G>T | p.Met1? | start_lost | Exon 1 of 2 | NP_937799.1 | ||
VHL | NR_176335.1 | n.73G>T | non_coding_transcript_exon_variant | Exon 1 of 4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152236Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000575 AC: 8AN: 139020Hom.: 0 AF XY: 0.0000538 AC XY: 4AN XY: 74312
GnomAD4 exome AF: 0.0000448 AC: 62AN: 1383052Hom.: 0 Cov.: 32 AF XY: 0.0000499 AC XY: 34AN XY: 680752
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152354Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74508
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 17, 2024 | Initiation codon variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (PMID: 10102622, 9751722, 9671762); This variant is associated with the following publications: (PMID: 9751722, 10102622, 9671762, 23541568, 30093976, 32191290, 33840814) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2018 | - - |
Von Hippel-Lindau syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 20, 2024 | This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 19, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 20, 2022 | 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 18, 2022 | Variant summary: VHL c.3G>T (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon (Met52). The variant allele was found at a frequency of 5.8e-05 in 139020 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3G>T has been reported in the literature in individuals affected with Breast cancer (Chan_2018). This report does not provide unequivocal conclusions about association of the variant with Von Hippel-Lindau Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function of this particular variant has been reported. There are, however, reports that a second conserved in-frame AUG acts as the start site for an alternate VHL product containing the functional domains in human cells, and knock-in mice that produce the shorter isoform appear phenotypically normal except for altered microtubule dynamics (Schoenfeld_1998, Iliopoulos_1998, Frew_2013). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2025 | This sequence change affects the initiator methionine of the VHL mRNA. The next in-frame methionine is located at codon 54. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. This variant is present in population databases (rs578091032, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with breast cancer and/or pilocytic astrocytoma (PMID: 30093976, 33840814). ClinVar contains an entry for this variant (Variation ID: 238106). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). 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. - |
Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 24, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at