NM_000551.4(VHL):c.241C>G (p.Pro81Ala) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Sep 19, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001379600.1

Allele description [Variation Report for NM_000551.4(VHL):c.241C>G (p.Pro81Ala)]

NM_000551.4(VHL):c.241C>G (p.Pro81Ala)

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.241C>G (p.Pro81Ala)
HGVS:
  • NC_000003.12:g.10142088C>G
  • NG_008212.3:g.5454C>G
  • NM_000551.4:c.241C>GMANE SELECT
  • NM_001354723.2:c.241C>G
  • NM_198156.3:c.241C>G
  • NP_000542.1:p.Pro81Ala
  • NP_001341652.1:p.Pro81Ala
  • NP_937799.1:p.Pro81Ala
  • LRG_322:g.5454C>G
  • NC_000003.11:g.10183772C>G
Protein change:
P81A
Molecular consequence:
  • NM_000551.4:c.241C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.241C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.241C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Erythrocytosis, familial, 2 (ECYT2)
Synonyms:
POLYCYTHEMIA, CHUVASH TYPE; POLYCYTHEMIA, VHL-DEPENDENT
Identifiers:
MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400
Name:
Von Hippel-Lindau syndrome (VHLS)
Synonyms:
VHL syndrome; Von Hippel-Lindau
Identifiers:
MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001577427Invitaecriteria provided, single submitter
Likely pathogenic
(Sep 19, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Genetic basis of congenital erythrocytosis: mutation update and online databases.

Bento C, Percy MJ, Gardie B, Maia TM, van Wijk R, Perrotta S, Della Ragione F, Almeida H, Rossi C, Girodon F, Aström M, Neumann D, Schnittger S, Landin B, Minkov M, Randi ML, Richard S, Casadevall N, Vainchenker W, Rives S, Hermouet S, Ribeiro ML, et al.

Hum Mutat. 2014 Jan;35(1):15-26. doi: 10.1002/humu.22448. Epub 2013 Oct 22.

PubMed [citation]
PMID:
24115288

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.

Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA.

FASEB J. 2011 Jun;25(6):2001-11. doi: 10.1096/fj.10-177378. Epub 2011 Mar 9.

PubMed [citation]
PMID:
21389259
PMCID:
PMC3159892
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001577427.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces proline with alanine at codon 81 of the VHL protein (p.Pro81Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with erythrocytosis (PMID: 24115288). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant disrupts the p.Pro81 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21389259, 27730413, 24134185, 22241717, 17102082, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 14, 2021

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