NM_000551.4(VHL):c.224TCT[1] (p.Phe76del) AND Von Hippel-Lindau syndrome

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Nov 9, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000208790.13

Allele description [Variation Report for NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)]

NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)

Gene:

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.224TCT[1] (p.Phe76del)

HGVS:

NC_000003.11:g.10183755_10183757del
NC_000003.12:g.10142071TCT[1]
NG_008212.3:g.5437TCT[1]
NM_000551.4:c.224TCT[1]MANE SELECT
NM_000551.4:c.227_229delTCT
NM_001354723.2:c.224TCT[1]
NM_198156.3:c.224TCT[1]
NP_000542.1:p.Phe76del
NP_001341652.1:p.Phe76del
NP_937799.1:p.Phe76del
LRG_322t1:c.227_229del
LRG_322:g.5437TCT[1]
NC_000003.11:g.10183755TCT[1]
NC_000003.11:g.10183755_10183757del
NC_000003.11:g.10183758_10183760delTCT
NM_000551.3:c.227_229del
NM_000551.3:c.227_229delTCT
NM_000551.4:c.227_229delMANE SELECT
NM_000551.4:c.227_229delTCTMANE SELECT
c.583C>T
p.[Phe76del]

Protein change:

F76del; GLN195TER

Links:

dbSNP: rs5030648

NCBI 1000 Genomes Browser:

rs5030648

Molecular consequence:

NM_000551.4:c.224TCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354723.2:c.224TCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198156.3:c.224TCT[1] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Von Hippel-Lindau syndrome (VHLS)
Synonyms:: VHL syndrome; Von Hippel-Lindau
Identifiers:: MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

Recent activity

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centrosomal protein of 164 kDa isoform X2 [Homo sapiens]
centrosomal protein of 164 kDa isoform X2 [Homo sapiens]
gi|2462523718|ref|XP_054224028.1|

Protein
PREDICTED: Homo sapiens centrosomal protein 164 (CEP164), transcript variant X48...
PREDICTED: Homo sapiens centrosomal protein 164 (CEP164), transcript variant X48, mRNA
gi|2217281790|ref|XM_047426604.1|

Nucleotide
centrosomal protein of 164 kDa isoform X40 [Homo sapiens]
centrosomal protein of 164 kDa isoform X40 [Homo sapiens]
gi|2462523802|ref|XP_054224070.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264675	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Pathogenic (Feb 26, 2016)	germline	clinical testing
SCV001192830	CIViC knowledgebase, Washington University School of Medicine	criteria provided, single submitter (Danos AM et al. (Genome Med 2019))	Pathogenic	germline	curation	PubMed (13) [See all records that cite these PMIDs] 26763786, 8641976, 21463266, 11409863, 20151405, 10761708, 22357542, 17024664, 7987306, 17661816, 25078357, 23143947, 31779674 https://civicdb, Citation Link,
SCV001365606	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Dec 3, 2019)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 29616089, 23011899, 17661816, 27539324, 27439424, 7987306, 23632291, 12114495, 27527340, 20567917, 20151405, 22357542, 18446368, 20064270, 24033266
SCV001499822	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512257	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175276	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 9, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 7987306, 8641976, 23143947, 23632291, 27527340, 29616089, 32179488, 33720516, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	21	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	2	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

Von Hippel-Lindau disease: an evaluation of natural history and functional disability.

Feletti A, Anglani M, Scarpa B, Schiavi F, Boaretto F, Zovato S, Taschin E, Gardi M, Zanoletti E, Piermarocchi S, Murgia A, Pavesi G, Opocher G.

Neuro Oncol. 2016 Jul;18(7):1011-20. doi: 10.1093/neuonc/nov313. Epub 2016 Jan 12.

PubMed [citation]

PMID:: 26763786
PMCID:: PMC4896541

Identification and in silico analysis of novel von Hippel-Lindau (VHL) gene variants from a large population.

Leonardi E, Martella M, Tosatto SC, Murgia A.

Ann Hum Genet. 2011 Jul;75(4):483-96. doi: 10.1111/j.1469-1809.2011.00647.x. Epub 2011 Apr 4.

PubMed [citation]

PMID:: 21463266

See all PubMed Citations (27)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264675.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	21	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		21	not provided	not provided	not provided

From CIViC knowledgebase, Washington University School of Medicine, SCV001192830.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (13)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365606.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (15)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	2	not provided

From Department of Molecular Diagnostics, Institute of Oncology Ljubljana, SCV001499822.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512257.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

ACMG classification criteria: PS4 strong, PM2 moderate, PM4 moderate, PM6 moderate, PP1 very strong

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV004175276.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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