NM_000551.4(VHL):c.416C>G (p.Ser139Cys) AND Von Hippel-Lindau syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Feb 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000123107.5

Allele description [Variation Report for NM_000551.4(VHL):c.416C>G (p.Ser139Cys)]

NM_000551.4(VHL):c.416C>G (p.Ser139Cys)

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.416C>G (p.Ser139Cys)

Other names:

p.S139C:TCT>TGT

HGVS:

NC_000003.12:g.10146589C>G
NG_008212.3:g.9955C>G
NG_046756.1:g.4351C>G
NM_000551.4:c.416C>GMANE SELECT
NM_001354723.2:c.*18-3198C>G
NM_198156.3:c.341-3198C>G
NP_000542.1:p.Ser139Cys
NP_000542.1:p.Ser139Cys
LRG_322t1:c.416C>G
LRG_322:g.9955C>G
LRG_322p1:p.Ser139Cys
NC_000003.11:g.10188273C>G
NM_000551.3:c.416C>G
NM_198156.2:c.341-3198C>G

Protein change:

S139C

Links:

dbSNP: rs587780732

NCBI 1000 Genomes Browser:

rs587780732

Molecular consequence:

NM_001354723.2:c.*18-3198C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3198C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.416C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

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
SCV000488489	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Apr 14, 2016)	unknown	clinical testing	Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004831968	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Feb 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000488489

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Apr 14, 2016)

unknown

clinical testing

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004831968

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Feb 5, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Counsyl, SCV000488489.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004831968.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces serine with cysteine at codon 139 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with VHL-related disorders in the literature. This variant has been identified in 23/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		7	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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