NM_000551.4(VHL):c.246C>T (p.Arg82=) AND Von Hippel-Lindau syndrome

Germline classification:: Benign (3 submissions)
Last evaluated:: Jun 25, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000206706.6

Allele description [Variation Report for NM_000551.4(VHL):c.246C>T (p.Arg82=)]

NM_000551.4(VHL):c.246C>T (p.Arg82=)

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.246C>T (p.Arg82=)

Other names:

p.R82R:CGC>CGT; NM_000551.4(VHL):c.246C>T; p.Arg82=

HGVS:

NC_000003.12:g.10142093C>T
NG_008212.3:g.5459C>T
NM_000551.4:c.246C>TMANE SELECT
NM_001354723.2:c.246C>T
NM_198156.3:c.246C>T
NP_000542.1:p.Arg82=
NP_000542.1:p.Arg82=
NP_001341652.1:p.Arg82=
NP_937799.1:p.Arg82=
LRG_322t1:c.246C>T
LRG_322:g.5459C>T
LRG_322p1:p.Arg82=
NC_000003.11:g.10183777C>T
NM_000551.3:c.246C>T
p.R82R

Links:

dbSNP: rs587780993

NCBI 1000 Genomes Browser:

rs587780993

Molecular consequence:

NM_000551.4:c.246C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354723.2:c.246C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_198156.3:c.246C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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Human tight junction protein occludin mRNA, complete cds
Human tight junction protein occludin mRNA, complete cds
gi|1322281|gb|U53823.1|HSU53823

Nucleotide
actin, partial [Colletotrichum sp. IVS-2014c]
actin, partial [Colletotrichum sp. IVS-2014c]
gi|631793068|gb|AHZ13915.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000487851	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely benign (Dec 1, 2015)	unknown	clinical testing	Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004841641	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Feb 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005187311	ClinGen VHL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen VHL VCEP ACMG Specifications VHL V1)	Benign (Jun 25, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000487851

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely benign
(Dec 1, 2015)

unknown

clinical testing

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004841641

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Feb 5, 2024)

germline

clinical testing

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

SCV005187311

ClinGen VHL Variant Curation Expert Panel, ClinGen

reviewed by expert panel

(ClinGen VHL VCEP ACMG Specifications VHL V1)

Benign
(Jun 25, 2024)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	45	not provided	not provided	108544	not provided	clinical testing, curation
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, SCV000487851.2

#	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, SCV004841641.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	45	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		45	not provided	not provided	not provided

From ClinGen VHL Variant Curation Expert Panel, ClinGen, SCV005187311.1

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

Description

The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0002832 (365/1179692 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).

#	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: Sep 29, 2024

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