NM_000551.4(VHL):c.154G>T (p.Glu52Ter) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jun 1, 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:: RCV000656989.11

Allele description [Variation Report for NM_000551.4(VHL):c.154G>T (p.Glu52Ter)]

NM_000551.4(VHL):c.154G>T (p.Glu52Ter)

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.154G>T (p.Glu52Ter)

Other names:

p.E52*:GAG>TAG

HGVS:

NC_000003.12:g.10142001G>T
NG_008212.3:g.5367G>T
NM_000551.4:c.154G>TMANE SELECT
NM_001354723.2:c.154G>T
NM_198156.3:c.154G>T
NP_000542.1:p.Glu52Ter
NP_000542.1:p.Glu52Ter
NP_001341652.1:p.Glu52Ter
NP_937799.1:p.Glu52Ter
LRG_322t1:c.154G>T
LRG_322:g.5367G>T
LRG_322p1:p.Glu52Ter
NC_000003.11:g.10183685G>T
NM_000551.3:c.154G>T
p.Glu52X

Protein change:

E52*

Links:

dbSNP: rs373068386

NCBI 1000 Genomes Browser:

rs373068386

Molecular consequence:

NM_000551.4:c.154G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354723.2:c.154G>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198156.3:c.154G>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000211825	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Jun 1, 2022)	germline	clinical testing	Citation Link,
SCV000712524	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (May 19, 2022)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 21463266, 10102622, 23541568, 26211615, 24583008, 10766184, 25966224, 9829912, 28454591, 29978187, 26681312, 25741868
SCV000805322	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 20, 2017)	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

SCV000211825

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Jun 1, 2022)

germline

clinical testing

Citation Link,

SCV000712524

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(May 19, 2022)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000805322

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 20, 2017)

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	not provided	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

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

Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity.

Blankenship C, Naglich JG, Whaley JM, Seizinger B, Kley N.

Oncogene. 1999 Feb 25;18(8):1529-35.

PubMed [citation]

PMID:: 10102622

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000211825.13

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

Description

Nonsense variant in a gene for which a downstream in-frame ATG produces an alternate clinically-relevant isoform, pVHL19, that may result in a functional protein (Iliopoulos 1998, Schoenfeld 1998, Blankenship 1999); Observed in individuals with hemangioblastoma, renal cancer, or pancreatic cancer in published literature, but also in several individuals without personal history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx (Leonardi 2011, Johns 2017, Carlo 2018, Sculco 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21463266, 27651169, 26681312, 28526081, 28454591, 28539463, 28873162, 29790589, 28492532, 29978187, 32994724, 10900011, 34566400, 35032816, 9751722, 9671762, 10102622)

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000712524.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Glu52X variant in VHL has been reported in at least 1 sporadic case with VHL-associated tumors (Leonardi 2011). It has also been identified in 3/94886 European chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs373068386). This nonsense variant leads to a premature termination codon at position 52, which is predicted to lead to a truncated or absent protein. However, two isoforms of the VHL protein are expressed in humans: the full length protein (pVHL30) and a shorter isoform (pVHL19), which is translated from the methionine residue at position 54 of pVHL30 (Robinson 2014). Both isoforms are reported to have tumor suppressor abilities (Blankenship 1999). The p.Glu52X variant would only be expected to impact the pVHL30 isoform, meaning that a functional VHL tumor suppressor (pVHL19) may still be produced. A mouse model lacking the long isoform of VHL did not have overt phenotypes, supporting that loss of pVHL30 may not be sufficient to cause von Hippel-Lindau (VHL) syndrome (Frew 2013). Nevertheless, several studies suggest that the pVHL19 and pVHL30 have unique cellular functions (Frew 2013, Minervini 2015), and loss of the pVHL30 isoform may lead to clinical manifestations. Only two other studies have reported loss of funtion (LoF) variants that impact only the pVHL30 isoform (Olschwang 1998, Fu 2015), and additional data would provide evidence to support the association of "pVHL30 only" LoF variants to VHL syndrome. In summary, while there is some suspicion for a pathogenic role due to its predicted impact, the clinical significance of the p.Glu52X variant is uncertain.

#	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 PreventionGenetics, part of Exact Sciences, SCV000805322.1

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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