NM_000551.4(VHL):c.150C>G (p.Ala50=) AND Von Hippel-Lindau syndrome

Germline classification:: Benign (4 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:: RCV001150099.11

Allele description [Variation Report for NM_000551.4(VHL):c.150C>G (p.Ala50=)]

NM_000551.4(VHL):c.150C>G (p.Ala50=)

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.150C>G (p.Ala50=)

Other names:

p.A50A:GCC>GCG; NM_000551.4(VHL):c.150C>G; p.Ala50=

HGVS:

NC_000003.12:g.10141997C>G
NG_008212.3:g.5363C>G
NM_000551.4:c.150C>GMANE SELECT
NM_001354723.2:c.150C>G
NM_198156.3:c.150C>G
NP_000542.1:p.Ala50=
NP_000542.1:p.Ala50=
NP_001341652.1:p.Ala50=
NP_937799.1:p.Ala50=
LRG_322t1:c.150C>G
LRG_322:g.5363C>G
LRG_322p1:p.Ala50=
NC_000003.11:g.10183681C>G
NM_000551.2:c.150C>G
NM_000551.3:c.150C>G
c.150C>G
p.A50A
p.Ala50Ala

Links:

dbSNP: rs61751580

NCBI 1000 Genomes Browser:

rs61751580

Molecular consequence:

NM_000551.4:c.150C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354723.2:c.150C>G - synonymous variant - [Sequence Ontology: SO:0001819]
NM_198156.3:c.150C>G - synonymous variant - [Sequence Ontology: SO:0001819]

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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Homo sapiens N-acylsphingosine amidohydrolase 1 (ASAH1), RefSeqGene on chromosome 8
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001311111	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Benign (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV001950148	Clinical Genomics Labs, University Health Network	no assertion criteria provided (ACMG Guidelines, 2015)	Likely benign (May 29, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004360951	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Sep 20, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005187305	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

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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, curation

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 Illumina Laboratory Services, Illumina, SCV001311111.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

#	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

From Clinical Genomics Labs, University Health Network, SCV001950148.1

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

From Color Diagnostics, LLC DBA Color Health, SCV004360951.1

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

From ClinGen VHL Variant Curation Expert Panel, ClinGen, SCV005187305.1

#	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.150C>G (p.Ala50=) is a synonymous (silent) variant that is not predicted by SpliceAI or VarSeak to impact splicing. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.0.0 is 0.001000 (1222/1163922 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: Oct 20, 2024

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