NM_000551.4(VHL):c.429C>T (p.Asp143=) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 12, 2023
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:: RCV000470382.10

Allele description [Variation Report for NM_000551.4(VHL):c.429C>T (p.Asp143=)]

NM_000551.4(VHL):c.429C>T (p.Asp143=)

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.429C>T (p.Asp143=)

HGVS:

NC_000003.12:g.10146602C>T
NG_008212.3:g.9968C>T
NG_046756.1:g.4364C>T
NM_000551.4:c.429C>TMANE SELECT
NM_001354723.2:c.*18-3185C>T
NM_198156.3:c.341-3185C>T
NP_000542.1:p.Asp143=
NP_000542.1:p.Asp143=
LRG_322t1:c.429C>T
LRG_322:g.9968C>T
LRG_322p1:p.Asp143=
NC_000003.11:g.10188286C>T
NM_000551.3:c.429C>T

Links:

dbSNP: rs773556807

NCBI 1000 Genomes Browser:

rs773556807

Molecular consequence:

NM_001354723.2:c.*18-3185C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3185C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.429C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000563217	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29891534, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000563217

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 12, 2023)

germline

clinical testing

PubMed (2)
[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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000563217.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change affects codon 143 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein. This variant is present in population databases (rs773556807, gnomAD 0.006%). This variant has been observed in individuals with autosomal recessive erythrocytosis (PMID: 29891534). This variant is also known as D143D. ClinVar contains an entry for this variant (Variation ID: 416990). Studies have shown that this variant alters VHL gene expression (PMID: 29891534; Invitae). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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.

#	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: Oct 20, 2024

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Relating variation to medicine