ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.191G>C (p.Arg64Pro)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000551.4(VHL):c.191G>C (p.Arg64Pro)
Variation ID: 2226 Accession: VCV000002226.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p25.3 3: 10142038 (GRCh38) [ NCBI UCSC ] 3: 10183722 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 9, 2016 Feb 28, 2024 Jan 5, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000551.4:c.191G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Arg64Pro missense NM_001354723.2:c.191G>C NP_001341652.1:p.Arg64Pro missense NM_198156.3:c.191G>C NP_937799.1:p.Arg64Pro missense NC_000003.12:g.10142038G>C NC_000003.11:g.10183722G>C NG_008212.3:g.5404G>C LRG_322:g.5404G>C LRG_322t1:c.191G>C LRG_322p1:p.Arg64Pro P40337:p.Arg64Pro - Protein change
- R64P
- Other names
- -
- Canonical SPDI
- NC_000003.12:10142037:G:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
-
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
802 | 1957 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Pathogenic (1) |
no assertion criteria provided
|
Jul 29, 1998 | RCV000002314.3 | |
Pathogenic (1) |
criteria provided, single submitter
|
Apr 17, 2019 | RCV000132356.4 | |
Pathogenic (1) |
criteria provided, single submitter
|
Aug 1, 2018 | RCV000208872.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 5, 2024 | RCV000475973.6 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 24, 2023 | RCV000679019.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
---|---|---|---|---|---|
Likely pathogenic
(Feb 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000805324.1
First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018 |
|
|
Pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004034858.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Also known as … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Also known as c.404G>A, p.(R105P); This variant is associated with the following publications: (PMID: 19408298, 18836774, 29748190, 21463266, 19336503, 9663592, 19808854, 17661816, 19576851, 17639058, 17102083, 20151405, 18043261, 26269449, 30877234, 28944243, 28646318, 11331612, 16452184, 15611064, 17700531, 12944410, 26846855, 32832168, 32487141, 24555745) (less)
|
|
Pathogenic
(Aug 01, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
|
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264666.2
First in ClinVar: Mar 09, 2016 Last updated: Apr 17, 2019 |
Number of individuals with the variant: 7
|
|
Pathogenic
(Apr 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000187445.7
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The p.R64P pathogenic mutation (also known as c.191G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at … (more)
The p.R64P pathogenic mutation (also known as c.191G>C), located in coding exon 1 of the VHL gene, results from a G to C substitution at nucleotide position 191. The arginine at codon 64 is replaced by proline, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals and/or families diagnosed with VHL (van der Harst E et al. Int J Cancer. 1998 Jul 29;77(3):337-40; Hoffman MA et al. Hum. Mol. Genet. 2001 May;10:1019-27; Hes FJ et al. Clin Genet. 2007 Aug;72(2):122-9; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Wittström E et al. Ophthalmic Genet. 2014 Jun;35:91-106). In addition, a 23-year-old female diagnosed with a neck PGL who had a family history of PCCs and clear cell renal cell carcinoma was found to carry this alteration, and her tumor showed LOH for the wild-type allele (Gaal J et al. J Clin Endocrinol Metab. 2009 Nov;94(11):4367-71). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Jan 05, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Von Hippel-Lindau syndrome
Chuvash polycythemia
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000553379.5
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 64 of the VHL protein (p.Arg64Pro). … (more)
This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 64 of the VHL protein (p.Arg64Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Von Hippel-Lindau (VHL) syndrome and pheochromocytoma (PMID: 9663592, 17102083, 17661816, 19336503, 24555745). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2226). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 11331612, 15611064, 16452184). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Jul 29, 1998)
|
no assertion criteria provided
Method: literature only
|
PHEOCHROMOCYTOMA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000022472.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
In an uncle and his nephew with apparently isolated pheochromocytoma (171300), van der Harst et al. (1998) found an arg64-to-pro (R64P) mutation in the VHL … (more)
In an uncle and his nephew with apparently isolated pheochromocytoma (171300), van der Harst et al. (1998) found an arg64-to-pro (R64P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by van der Harst et al. (1998) that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also 608537.0016). (less)
|
Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Genotype-phenotype correlations, and retinal function and structure in von Hippel-Lindau disease. | Wittström E | Ophthalmic genetics | 2014 | PMID: 24555745 |
Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population. | Leonardi E | Annals of human genetics | 2011 | PMID: 21463266 |
Parasympathetic paragangliomas are part of the Von Hippel-Lindau syndrome. | Gaal J | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19808854 |
Head and neck paragangliomas in von Hippel-Lindau disease and multiple endocrine neoplasia type 2. | Boedeker CC | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19336503 |
Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification. | Hes FJ | Clinical genetics | 2007 | PMID: 17661816 |
Frequent genetic changes in childhood pheochromocytomas. | De Krijger RR | Annals of the New York Academy of Sciences | 2006 | PMID: 17102083 |
Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. | Kurban G | Cancer research | 2006 | PMID: 16452184 |
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 |
von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF. | Hoffman MA | Human molecular genetics | 2001 | PMID: 11331612 |
Germline mutations in the vhl gene in patients presenting with phaeochromocytomas. | van der Harst E | International journal of cancer | 1998 | PMID: 9663592 |
Text-mined citations for rs104893826 ...
HelpRecord last updated Mar 11, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.