ClinVar Genomic variation as it relates to human health
NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)
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
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NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)
Variation ID: 223166 Accession: VCV000223166.26
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 3p25.3 3: 10142071-10142073 (GRCh38) [ NCBI UCSC ] 3: 10183755-10183757 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Dec 13, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000551.4:c.224TCT[1] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000542.1:p.Phe76del inframe deletion NM_000551.4:c.227_229del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000551.4:c.227_229delTCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000551.3:c.227_229delTCT NM_001354723.2:c.224TCT[1] NP_001341652.1:p.Phe76del inframe deletion NM_198156.3:c.224TCT[1] NP_937799.1:p.Phe76del inframe deletion NC_000003.12:g.10142071TCT[1] NC_000003.11:g.10183755TCT[1] NG_008212.3:g.5437TCT[1] LRG_322:g.5437TCT[1] LRG_322t1:c.227_229del - Protein change
- F76del
- Other names
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- Canonical SPDI
- NC_000003.12:10142070:TCTTCT:TCT
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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VHL | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
790 | 1943 |
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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2023 | RCV000469401.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 28, 2019 | RCV002444839.1 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 9, 2022 | RCV000208790.11 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 30, 2021 | RCV000679023.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 11, 2022 | RCV003389711.4 |
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. |
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Pathogenic
(-)
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criteria provided, single submitter
Method: curation
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von Hippel-Lindau disease
Associated Phenotypes (From HPO):
(more...)
Affected status: unknown
Allele origin:
germline
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CIViC knowledgebase, Washington University School of Medicine
Accession: SCV001192830.1
First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020 |
Comment:
The inframe variant, F76del, is pathogenic for Von Hippel-Lindau Disease. EID5682 shows a large family with the variant cosegregating with affected individuals (PP1). However, confirmed … (more)
The inframe variant, F76del, is pathogenic for Von Hippel-Lindau Disease. EID5682 shows a large family with the variant cosegregating with affected individuals (PP1). However, confirmed de novo mutations are also described EID5340 (PS2). Both are supported by several other reports with familial and sporadic VHL and this variant. This inframe deletion is not in a repetitive region (PM4) and absent from gnomAD v2.1 (PM2). (less)
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Pathogenic
(Dec 03, 2019)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV001365606.1
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
The p.Phe76del variant in VHL has been reported in >15 individuals with clinical features of Von Hippel-Lindau syndrome and segregated with disease in >5 affected … (more)
The p.Phe76del variant in VHL has been reported in >15 individuals with clinical features of Von Hippel-Lindau syndrome and segregated with disease in >5 affected individuals from several families (Crossey 1994, Cybulski 2002, Gomy 2010, Hes 2007, Jia 2013, Lee 2016, Nordstrom-Obrien 2010, Pandit 2016, Rasmussen 2010, Wang 2018, Wong 2016, Wu 2012, Zhang 2008). It was also identified as a de novo occurrence in 1 individual, though maternity and paternity were not confirmed (Jia 2013). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 223166) and was absent from large population studies. This variant is a deletion of 1 amino acid at position 76 and is not predicted to alter the protein reading-frame. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindau syndrome. ACMG/AMP criteria applied: PS4, PM2, PM6, PP1_Moderate, PM4_Supporting. (less)
Number of individuals with the variant: 2
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Pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499822.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Pathogenic
(Jul 13, 2021)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512257.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate, PP1 very strong
Geographic origin: Brazil
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Pathogenic
(Sep 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002734017.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.227_229delTCT pathogenic mutation (also known as c.226_228del TTC or p.F76del) is located in coding exon 1 of the VHL gene. This pathogenic mutation results … (more)
The c.227_229delTCT pathogenic mutation (also known as c.226_228del TTC or p.F76del) is located in coding exon 1 of the VHL gene. This pathogenic mutation results from an in-frame TCT deletion at nucleotide positions 227 to 229. This results in the in-frame deletion of a phenylalanine at codon 76. This pathogenic variant has been identified in numerous individuals and families diagnosed with VHL (Rocha J et al. J. Med. Genet. 2003 Mar; 40(3):e31; Sgambati M et al. Am. J. Hum. Genet. 2000 Jan; 66(1):84-91; Gomy I et al. Fam. Cancer. 2010 Dec; 9(4):635-42; Hes F et al. Clin. Genet. 2007 Aug; 72(2):122-9; Rasmussen A et al. BMC Med. Genet. 2010 Jan 12;11:4; Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23; Wong M et al. Chin J Cancer. 2016 Aug;35:79; Wang Y et al. Oncol Lett. 2018 Apr;15:4882-4890). Molecular dynamics studies indicate that the phenyalanine at amino acid position 76, which is deleted by this alteration, plays a key role in the structural integrity of the beta-domain of the VHL protein (Limaverde-Sousa G et al. Proteins. 2013 Feb; 81(2):349-63). Of note, this pathogenic variant may be referred to as c.224_226delTCT in some literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Nov 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001774350.3
First in ClinVar: Aug 07, 2021 Last updated: Mar 04, 2023 |
Comment:
In-frame deletion of 1 amino acid in a non-repeat region in the critical beta sandwich region of the beta domain (Yuen 2009); Not observed in … (more)
In-frame deletion of 1 amino acid in a non-repeat region in the critical beta sandwich region of the beta domain (Yuen 2009); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on protein structure/function; Also known as c.440_442del, p.(F147del); p.(F117del); This variant is associated with the following publications: (PMID: 7987306, 20064270, 20567917, 12624160, 8730290, 8634692, 9829911, 29961792, 30072823, 31528828, 27682873, 28036268, 27539324, 27527340, 27439424, 12114495, 17661816, 18446368, 20151405, 22357542, 7728151, 7553625, 8956040, 9829912, 10631138, 8641976, 7977367, 23632291, 25867206, 23011899, 11331613, 29124493, 29616089, 29748190, 32179488, 33720516, 33107222, 32003155) (less)
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Pathogenic
(Sep 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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VHL-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000805328.2
First in ClinVar: Sep 14, 2018 Last updated: Nov 20, 2023 |
Comment:
The VHL c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant has been previously reported in the heterozygous state in individuals … (more)
The VHL c.227_229delTCT variant is predicted to result in an in-frame deletion (p.Phe76del). This variant has been previously reported in the heterozygous state in individuals or affected family members with Von Hippel-Lindau syndrome (see for example Hes et al. 2007. PubMed ID: 17661816; Ong et al. 2007. PubMed ID: 17024664, Supplementary Table S1; Nordstrom-O'Brien et al. 2010. PubMed ID: 20151405, Supplementary Table S1; Leonardi et al. 2011. PubMed ID: 21463266, Supplementary material; Wu et al. 2012. PubMed ID: 22357542; also reported with differences in the cDNA nomenclature in Wong et al. 2016. PubMed ID: 27527340; Pandit et al. 2016. PubMed ID: 27539324; Lomte et al. 2018. PubMed ID: 29124493). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Nov 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Von Hippel-Lindau syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV004175276.1
First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023 |
Comment:
The VHL c.227_229del variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM4, PM6, PP1, PP4) The VHL c.227_229del variant results in an inframe deletion in … (more)
The VHL c.227_229del variant is classified as Likely Pathogenic (PS4_Moderate, PM2, PM4, PM6, PP1, PP4) The VHL c.227_229del variant results in an inframe deletion in exon 1/3. This variant has been reported in 9 unrelated individuals with a clinical presentation of von Hippel-Lindau syndrome (PMID: 7987306, 27527340, 29616089, 32179488, 33720516) (PS4_Moderate). This variant is absent from population databases (PM2). This variant is predicted to alter the length of the protein produced by this gene due to an inframe deletion variant in a nonrepeat region (PM4). This variant has been identified as a de novo variant in at least one affected patient with no family history of this condition (PMID: 8641976, 23632291) (PM6). This variant is reported to co-segregate with disease in one family (PMID: 23143947) (PP1). The clinical features of this case are highly specific for the VHL gene (PP4). This variant is in dbSNP (rs5030648), has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID:223166) and has been reported as disease-causing in HGMD (CD941805). (less)
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Pathogenic
(Dec 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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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
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Invitae
Accession: SCV000553395.9
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the VHL protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. … (more)
This variant, c.227_229del, results in the deletion of 1 amino acid(s) of the VHL protein (p.Phe76del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Hippel-Lindau syndrome (PMID: 12114495, 17661816, 18446368, 20064270, 20151405, 20567917, 22357542, 23632291, 27439424, 27527340). 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: 223166). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 26, 2016)
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no assertion criteria provided
Method: clinical testing
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Von Hippel-Lindau syndrome
Affected status: yes
Allele origin:
germline
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Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Accession: SCV000264675.1
First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016 |
Number of individuals with the variant: 21
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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 |
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Genotype-phenotype correlation in von Hippel-Lindau disease. | Reich M | Acta ophthalmologica | 2021 | PMID: 33720516 |
Novel and recurrent germline mutations in the VHL gene in 5 Arab patients with Von Hippel-Lindau disease. | Faiyaz-Ul-Haque M | Cancer genetics | 2020 | PMID: 32179488 |
Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. | Wang Y | Oncology letters | 2018 | PMID: 29616089 |
Genotype phenotype correlation in Asian Indian von Hippel-Lindau (VHL) syndrome patients with pheochromocytoma/paraganglioma. | Lomte N | Familial cancer | 2018 | PMID: 29124493 |
Germline mutations and genotype-phenotype correlation in Asian Indian patients with pheochromocytoma and paraganglioma. | Pandit R | European journal of endocrinology | 2016 | PMID: 27539324 |
Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome. | Wong M | Chinese journal of cancer | 2016 | PMID: 27527340 |
Genotype-phenotype analysis of von Hippel-Lindau syndrome in Korean families: HIF-α binding site missense mutations elevate age-specific risk for CNS hemangioblastoma. | Lee JS | BMC medical genetics | 2016 | PMID: 27439424 |
Von Hippel-Lindau disease: an evaluation of natural history and functional disability. | Feletti A | Neuro-oncology | 2016 | PMID: 26763786 |
A deletion mutation of the VHL gene associated with a patient with sporadic von Hippel-Lindau disease. | Jia D | Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia | 2013 | PMID: 23632291 |
Clinical and mutation analysis of four Chinese families with von Hippel-Lindau disease. | Chen J | Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico | 2013 | PMID: 23143947 |
Simulation of the mutation F76del on the von Hippel-Lindau tumor suppressor protein: mechanism of the disease and implications for drug development. | Limaverde-Sousa G | Proteins | 2013 | PMID: 23011899 |
Family history of von Hippel-Lindau disease was uncommon in Chinese patients: suggesting the higher frequency of de novo mutations in VHL gene in these patients. | Wu P | Journal of human genetics | 2012 | PMID: 22357542 |
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 |
Clinical and molecular characterization of Brazilian families with von Hippel-Lindau disease: a need for delineating genotype-phenotype correlation. | Gomy I | Familial cancer | 2010 | PMID: 20567917 |
Genetic analysis of von Hippel-Lindau disease. | Nordstrom-O'Brien M | Human mutation | 2010 | PMID: 20151405 |
Uptake of genetic testing and long-term tumor surveillance in von Hippel-Lindau disease. | Rasmussen A | BMC medical genetics | 2010 | PMID: 20064270 |
Germline mutations in the von Hippel-Lindau disease (VHL) gene in mainland Chinese families. | Zhang J | Journal of cancer research and clinical oncology | 2008 | PMID: 18446368 |
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 |
Genotype-phenotype correlations in von Hippel-Lindau disease. | Ong KR | Human mutation | 2007 | PMID: 17024664 |
High frequency of novel germline mutations in the VHL gene in the heterogeneous population of Brazil. | Rocha JC | Journal of medical genetics | 2003 | PMID: 12624160 |
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 |
DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations. | Klein B | Human genetics | 2001 | PMID: 11409863 |
Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: an extended study of 77 families. | Yoshida M | Japanese journal of cancer research : Gann | 2000 | PMID: 10761708 |
Mosaicism in von Hippel-Lindau disease: lessons from kindreds with germline mutations identified in offspring with mosaic parents. | Sgambati MT | American journal of human genetics | 2000 | PMID: 10631138 |
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma. | Olschwang S | Human mutation | 1998 | PMID: 9829912 |
Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene. | Stolle C | Human mutation | 1998 | PMID: 9829911 |
Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. | Zbar B | Human mutation | 1996 | PMID: 8956040 |
Molecular genetic diagnosis of von Hippel-Lindau disease: analysis of five Japanese families. | Kanno H | Japanese journal of cancer research : Gann | 1996 | PMID: 8641976 |
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 |
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Text-mined citations for rs5030648 ...
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.