NM_000551.4(VHL):c.598C>T (p.Arg200Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 2, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000161094.12

Allele description [Variation Report for NM_000551.4(VHL):c.598C>T (p.Arg200Trp)]

NM_000551.4(VHL):c.598C>T (p.Arg200Trp)

Genes:

LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [Gene]
VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.598C>T (p.Arg200Trp)

Other names:

p.R200W:CGG>TGG

HGVS:

NC_000003.12:g.10149921C>T
NG_008212.3:g.13287C>T
NG_046756.1:g.7683C>T
NM_000551.4:c.598C>TMANE SELECT
NM_001354723.2:c.*152C>T
NM_198156.3:c.475C>T
NP_000542.1:p.Arg200Trp
NP_000542.1:p.Arg200Trp
NP_937799.1:p.Arg159Trp
LRG_322t1:c.598C>T
LRG_322:g.13287C>T
LRG_322p1:p.Arg200Trp
NC_000003.11:g.10191605C>T
NM_000551.2:c.598C>T
NM_000551.3:c.598C>T
P40337:p.Arg200Trp
p.[Arg200Trp]

Protein change:

R159W; ARG200TRP

Links:

UniProtKB: P40337#VAR_005779; OMIM: 608537.0019; dbSNP: rs28940298

NCBI 1000 Genomes Browser:

rs28940298

Molecular consequence:

NM_001354723.2:c.*152C>T - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.598C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.475C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000205377	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 2, 2023)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 12415268, 15574766, 17992257, 21993671, 23015148, 21606165, 19030229, 18836774, 14726398, 12393546, 16210343, 8956040, 11987242, 25371412, 9829912, 31132167, 25741868
SCV000211829	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 26, 2021)	germline	clinical testing	Citation Link,
SCV001449948	Clinical Genetics and Genomics, Karolinska University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 14, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000205377

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 2, 2023)

germline

clinical testing

PubMed (17)
[See all records that cite these PMIDs]

SCV000211829

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 26, 2021)

germline

clinical testing

Citation Link,

SCV001449948

Clinical Genetics and Genomics, Karolinska University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 14, 2019)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia.

Ang SO, Chen H, Hirota K, Gordeuk VR, Jelinek J, Guan Y, Liu E, Sergueeva AI, Miasnikova GY, Mole D, Maxwell PH, Stockton DW, Semenza GL, Prchal JT.

Nat Genet. 2002 Dec;32(4):614-21. Epub 2002 Nov 4.

PubMed [citation]

PMID:: 12415268

In vitro and in vivo models analyzing von Hippel-Lindau disease-specific mutations.

Rathmell WK, Hickey MM, Bezman NA, Chmielecki CA, Carraway NC, Simon MC.

Cancer Res. 2004 Dec 1;64(23):8595-603.

PubMed [citation]

PMID:: 15574766

See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000205377.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The p.Arg200Trp variant in VHL has not been reported in the heterozygous state in individuals with paragangliomas, pheochromocytomas, or von Hippel-Lindau syndrome (Ang 2002 PMID: 12415268, Pastore 2003 PMID: 12393546, Gordeuk 2004 PMID: 14726398, Miasnikova 2011 PMID: 21606165) or in individuals with haemangioblastoma (Woodward 2007 PMID: 17264095). However, it is a well-established pathogenic variant in the homozygous state for autosomal recessive familial erythrocytosis, also known as Chuvash polycythemia (Ang 2002 PMID: 12415268, Gordeuk 2004 PMID: 14726398, Perrota 2006 PMID: 16210343, Mallik 2019 PMID: 31132167). It has also been identified in 0.065% (20/30604) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 2232). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg200Trp variant is uncertain as it relates to paragangliomas, pheochromocytomas, and von Hippel-Lindau syndrome. ACMG/AMP Criteria applied: PM2_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		not provided	not provided	not provided	not provided

From GeneDx, SCV000211829.13

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

Description

Published functional studies demonstrate a damaging effect: mice homozygous for variant showed similar phenotype to patients homozygous for the variant (Hickey 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; While this variant is considered pathogenic for autosomal recessive Chuvash polycythemia, there is no evidence that it causes increased risk for von Hippel Lindau disease (Pastore 2003a, Pastore 2003b, Woodward 2007, Miasnikova 2011); This variant is associated with the following publications: (PMID: 27568332, 15574766, 25637381, 21876117, 21993671, 27518686, 11987242, 29489754, 31132167, 19030229, 23015148, 18836774, 24728327, 8956040, 25371412, 17992257, 12415268, 21606165, 23403324, 9829912, 27651169, 12844285, 12393546, 14726398, 28400504, 28104701, 26556299, 29741264, 29790589, 16210343, 19494350, 31568062, 12702509, 30787465)

#	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 Clinical Genetics and Genomics, Karolinska University Hospital, SCV001449948.1

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

Last Updated: May 7, 2024

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