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:: RCV002525827.2

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

Recent activity

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albA [Pyrococcus furiosus DSM 3638]
albA [Pyrococcus furiosus DSM 3638]
Gene ID:1469760

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003525092	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 5, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10761708, 17001110, 27527340, 9829912, 15300849, 21384277, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003525092

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 5, 2022)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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 Invitae, SCV003525092.2

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

#	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: Feb 28, 2024

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