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NM_000551.4(VHL):c.393C>A (p.Asn131Lys) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Feb 5, 2022
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:
RCV002525827.3

Allele description [Variation Report for NM_000551.4(VHL):c.393C>A (p.Asn131Lys)]

NM_000551.4(VHL):c.393C>A (p.Asn131Lys)

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.393C>A (p.Asn131Lys)
HGVS:
  • NC_000003.12:g.10146566C>A
  • NG_008212.3:g.9932C>A
  • NG_046756.1:g.4328C>A
  • NM_000551.4:c.393C>AMANE SELECT
  • NM_001354723.2:c.*18-3221C>A
  • NM_198156.3:c.341-3221C>A
  • NP_000542.1:p.Asn131Lys
  • NP_000542.1:p.Asn131Lys
  • LRG_322t1:c.393C>A
  • LRG_322:g.9932C>A
  • LRG_322p1:p.Asn131Lys
  • NC_000003.11:g.10188250C>A
  • NM_000551.3:c.393C>A
Protein change:
N131K
Links:
dbSNP: rs1064794272
NCBI 1000 Genomes Browser:
rs1064794272
Molecular consequence:
  • NM_001354723.2:c.*18-3221C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3221C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.4:c.393C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Chuvash polycythemia
Synonyms:
POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
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

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003525092Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Feb 5, 2022) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: an extended study of 77 families.

Yoshida M, Ashida S, Kondo K, Kobayashi K, Kanno H, Shinohara N, Shitara N, Kishida T, Kawakami S, Baba M, Yamamoto I, Hosaka M, Shuin T, Yao M.

Jpn J Cancer Res. 2000 Feb;91(2):204-12.

PubMed [citation]
PMID:
10761708
PMCID:
PMC5926327

The N131S mutation in the von Hippel-Lindau gene in a Japanese family with pheochromocytoma and hemangioblastomas.

Imanaka M, Iida K, Takahashi K, Tsuji K, Nishizawa H, Fukuoka H, Takeno R, Takahashi Y, Okimura Y, Kaji H, Chihara K.

Endocr J. 2006 Dec;53(6):819-27. Epub 2006 Sep 26.

PubMed [citation]
PMID:
17001110
See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003525092.2

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn131 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10761708, 17001110, 21384277, 27527340; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 420074). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 9829912, 15300849, 21384277). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 131 of the VHL protein (p.Asn131Lys).

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

Last Updated: Sep 29, 2024