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NM_000551.4(VHL):c.414A>G (p.Pro138=) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 17, 2021
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV000216698.5

Allele description [Variation Report for NM_000551.4(VHL):c.414A>G (p.Pro138=)]

NM_000551.4(VHL):c.414A>G (p.Pro138=)

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.414A>G (p.Pro138=)
Other names:
P138P
HGVS:
  • NC_000003.12:g.10146587A>G
  • NG_008212.3:g.9953A>G
  • NG_046756.1:g.4349A>G
  • NM_000551.4:c.414A>GMANE SELECT
  • NM_001354723.2:c.*18-3200A>G
  • NM_198156.3:c.341-3200A>G
  • NP_000542.1:p.Pro138=
  • NP_000542.1:p.Pro138=
  • LRG_322t1:c.414A>G
  • LRG_322:g.9953A>G
  • LRG_322p1:p.Pro138=
  • NC_000003.11:g.10188271A>G
  • NM_000551.3:c.414A>G
  • p.[Pro138=]
Protein change:
PRO138PRO
Links:
OMIM: 608537.0033; dbSNP: rs869025648
NCBI 1000 Genomes Browser:
rs869025648
Molecular consequence:
  • NM_001354723.2:c.*18-3200A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3200A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.4:c.414A>G - synonymous variant - [Sequence Ontology: SO:0001819]
Functional consequence:
sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000276962Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Dec 17, 2021) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Lenglet M, Robriquet F, Schwarz K, Camps C, Couturier A, Hoogewijs D, Buffet A, Knight SJL, Gad S, Couvé S, Chesnel F, Pacault M, Lindenbaum P, Job S, Dumont S, Besnard T, Cornec M, Dreau H, Pentony M, Kvikstad E, Deveaux S, Burnichon N, et al.

Blood. 2018 Aug 2;132(5):469-483. doi: 10.1182/blood-2018-03-838235. Epub 2018 Jun 11.

PubMed [citation]
PMID:
29891534

Synonymous but Not Silent: A Synonymous VHL Variant in Exon 2 Confers Susceptibility to Familial Pheochromocytoma and von Hippel-Lindau Disease.

Flores SK, Cheng Z, Jasper AM, Natori K, Okamoto T, Tanabe A, Gotoh K, Shibata H, Sakurai A, Nakai T, Wang X, Zethoven M, Balachander S, Aita Y, Young W, Zheng S, Takekoshi K, Nakamura E, Tothill RW, Aguiar RCT, Dahia PLM.

J Clin Endocrinol Metab. 2019 Sep 1;104(9):3826-3834. doi: 10.1210/jc.2019-00235.

PubMed [citation]
PMID:
30946460
PMCID:
PMC6660912
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000276962.9

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The c.414A>G pathogenic mutation (also known as p.P138P), located in coding exon 2 of the VHL gene, results from an A to G substitution at nucleotide position 414. This nucleotide substitution does not change the proline at codon 138. This alteration has been identified in multiple individuals affected with pheochromocytomas, paragangliomas and/or von Hippel-Lindau syndrome (Ambry internal data, Ambry personal communication; Lenglet M et al. Blood. 2018 Aug;132:469-483; Flores SK et al. J Clin Endocrinol Metab, 2019 Apr;:; Liu F et al. BMC Med Genet, 2020 02;21:42; Ma X et al. Front Endocrinol (Lausanne), 2020 Dec;11:574662; Yonamine M et al. Cancers (Basel), 2021 Aug;13:). RT-PCR analysis of patient samples and mini gene assays show this alteration leads to skipping of exon 2 (Lenglet M et al. Blood. 2018 Aug;132:469-483) and internal RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This nucleotide position is poorly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024