This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant has been reported in the literature and is not present in population databases. This variant was reported in several families of various ethnic backgrounds affected with Von Hippel-Lindau (VHL) syndrome (PMID: 7987306, 10567493, 12114495, 22799452, 25282218). This variant is also known as Ser136Leu in the literature. ClinVar contains an entry for this variant (RCV000161083). This variant falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein. Other missense changes reported in suspected VHL cases include p.Ser65Trp and p.Ser65Pro, as well as several other missense variants within the same linker region of the protein. Furthermore, experimental studies have shown that missense changes in this region, including p.Ser65Leu, are deficient in promoting the degradation of the alpha subunit of the hypoxia-inducible transcription factor (PMID: 15611064). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 4
- First in ClinVar:
- Oct 11, 2015
- Most recent Submission:
- Feb 7, 2023
- Last evaluated:
- Aug 30, 2021
- Accession:
- VCV000182975.7
- Variation ID:
- 182975
- Description:
- single nucleotide variant
Help
NM_000551.4(VHL):c.194C>T (p.Ser65Leu)
- Allele ID
- 180112
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 3p25.3
- Genomic location
- 3: 10142041 (GRCh38) GRCh38 UCSC
- 3: 10183725 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000551.4:c.194C>T MANE Select NP_000542.1:p.Ser65Leu missense NM_001354723.2:c.194C>T NP_001341652.1:p.Ser65Leu missense NM_198156.3:c.194C>T NP_937799.1:p.Ser65Leu missense NC_000003.12:g.10142041C>T NC_000003.11:g.10183725C>T NG_008212.3:g.5407C>T LRG_322:g.5407C>T LRG_322t1:c.194C>T LRG_322p1:p.Ser65Leu P40337:p.Ser65Leu - Protein change
- S65L
- Other names
- -
- Canonical SPDI
- NC_000003.12:10142040:C:T
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA020104
- UniProtKB: P40337#VAR_005672
- dbSNP: rs5030826
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 1 | criteria provided, single submitter | Apr 24, 2015 | RCV000199197.1 | |
| Pathogenic | 1 | criteria provided, single submitter | Jan 1, 2017 | RCV000626711.2 | |
| Pathogenic | 2 | criteria provided, single submitter | Aug 30, 2021 | RCV001389259.4 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
729 | 1795 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Apr 24, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000253855.2
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Comment:
This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a … (more)
This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant has been reported in the literature and is not present in population databases. This variant was reported in several families of various ethnic backgrounds affected with Von Hippel-Lindau (VHL) syndrome (PMID: 7987306, 10567493, 12114495, 22799452, 25282218). This variant is also known as Ser136Leu in the literature. ClinVar contains an entry for this variant (RCV000161083). This variant falls in a mutational 'hotspot', which is defined as a clustering of plausible observations within a localized region of the protein. Other missense changes reported in suspected VHL cases include p.Ser65Trp and p.Ser65Pro, as well as several other missense variants within the same linker region of the protein. Furthermore, experimental studies have shown that missense changes in this region, including p.Ser65Leu, are deficient in promoting the degradation of the alpha subunit of the hypoxia-inducible transcription factor (PMID: 15611064). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Jan 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000747414.1
First in ClinVar: May 12, 2018 Last updated: May 12, 2018 |
|
|
|
Pathogenic
(Aug 30, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001590551.3
First in ClinVar: May 10, 2021 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a … (more)
This sequence change replaces serine with leucine at codon 65 of the VHL protein (p.Ser65Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with clinical features of von Hippel-Lindau syndrome (PMID: 7987306, 10567493, 12114495, 22799452). This variant is also known as Ser136Leu. ClinVar contains an entry for this variant (Variation ID: 182975). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects VHL function (PMID: 15611064). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 7987306, 22799452, 23384228). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
not provided
(-)
|
no assertion provided
Method: phenotyping only
|
Affected status: unknown
Allele origin:
unknown
|
GenomeConnect - Invitae Patient Insights Network
Accession: SCV001749427.1
First in ClinVar: Jul 18, 2021 Last updated: Jul 18, 2021 |
Comment:
Variant interpreted as Pathogenic and reported on 06-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report … (more)
Variant interpreted as Pathogenic and reported on 06-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Abnormal retinal morphology (present) , Abnormality of the neck (present) , Abnormal skull morphology (present) , Asthma (present) , Immunodeficiency (present) , Abnormal inflammatory response … (more)
Abnormal retinal morphology (present) , Abnormality of the neck (present) , Abnormal skull morphology (present) , Asthma (present) , Immunodeficiency (present) , Abnormal inflammatory response (present) , Recurrent infections (present) , Abnormality of the pancreas (present) , Abnormal stomach morphology (present) , Abnormal muscle physiology (present) , Abnormality of the somatic nervous system (present) , Abnormality of the musculature of the limbs (present) , Abnormal morphology of the pelvis musculature (present) , Abnormal renal physiology (present) , Abnormal renal morphology (present) , Abnormality of urine homeostasis (present) , Abnormality of the nervous system (present) , Memory impairment (present) , Seizure (present) , Anxiety (present) , Hallucinations (present) , Pregnancy history (present) , Maternal teratogenic exposure (present) , Premature birth (present) (less)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: male
Testing laboratory: Invitae
Date variant was reported to submitter: 2020-06-17
Testing laboratory interpretation: Pathogenic
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Mosaicism in von Hippel-Lindau disease with severe renal manifestations. | Wu P | Clinical genetics | 2013 | PMID: 23384228 |
| Identification of 3 novel VHL germ-line mutations in Danish VHL patients. | Dandanell M | BMC medical genetics | 2012 | PMID: 22799452 |
| Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex. | Miller F | The Journal of biological chemistry | 2005 | PMID: 15611064 |
| Germline mutations in the von Hippel-Lindau (VHL) gene in patients from Poland: disease presentation in patients with deletions of the entire VHL gene. | Cybulski C | Journal of medical genetics | 2002 | PMID: 12114495 |
| The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system. | Gläsker S | Journal of neurology, neurosurgery, and psychiatry | 1999 | PMID: 10567493 |
| Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. | Chen F | Human mutation | 1995 | PMID: 7728151 |
| Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. | Crossey PA | Human molecular genetics | 1994 | PMID: 7987306 |
Text-mined citations for rs5030826...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Aug 06, 2023