NM_000551.4(VHL):c.233A>G (p.Asn78Ser) AND Von Hippel-Lindau syndrome

Germline classification:: Pathogenic (5 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:: RCV000079207.21

Allele description [Variation Report for NM_000551.4(VHL):c.233A>G (p.Asn78Ser)]

NM_000551.4(VHL):c.233A>G (p.Asn78Ser)

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.233A>G (p.Asn78Ser)

Other names:

NM_000551.4(VHL):c.233A>G

HGVS:

NC_000003.12:g.10142080A>G
NG_008212.3:g.5446A>G
NM_000551.4:c.233A>GMANE SELECT
NM_001354723.2:c.233A>G
NM_198156.3:c.233A>G
NP_000542.1:p.Asn78Ser
NP_000542.1:p.Asn78Ser
NP_001341652.1:p.Asn78Ser
NP_937799.1:p.Asn78Ser
LRG_322t1:c.233A>G
LRG_322:g.5446A>G
LRG_322p1:p.Asn78Ser
NC_000003.11:g.10183764A>G
NM_000551.3:c.233A>G
P40337:p.Asn78Ser
p.[Asn78Ser]

Protein change:

N78S

Links:

UniProtKB: P40337#VAR_005683; dbSNP: rs5030804

NCBI 1000 Genomes Browser:

rs5030804

Molecular consequence:

NM_000551.4:c.233A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.233A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.233A>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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Homo sapiens fer-1-like 4 (C. elegans), mRNA (cDNA clone IMAGE:5169552)
Homo sapiens fer-1-like 4 (C. elegans), mRNA (cDNA clone IMAGE:5169552)
gi|20455825|gb|BC029951.1|

Nucleotide
Rattus norvegicus spermatogenesis associated 6, mRNA (cDNA clone IMAGE:7457163),...
Rattus norvegicus spermatogenesis associated 6, mRNA (cDNA clone IMAGE:7457163), partial cds
gi|165970645|gb|BC158581.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264678	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Pathogenic (Feb 26, 2016)	germline	clinical testing
SCV000785647	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Pathogenic (Oct 19, 2017)	unknown	clinical testing	PubMed (14) [See all records that cite these PMIDs] 23842656, 28388566, 26503325, 15109448, 12510195, 8707293, 10408776, 11739384, 21454469, 19602254, 11309459, 21715564, 16775032, 11331613 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001442590	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 28, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12114495, 12202531, 15109448, 8956040, 19602254, 21454469 Citation Link,
SCV001950147	Clinical Genomics Labs, University Health Network	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005187307	ClinGen VHL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen VHL VCEP ACMG Specifications VHL V1)	Pathogenic (Jun 25, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] 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	yes	5	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

p.N78S and p.R161Q germline mutations of the VHL gene are present in von Hippel-Lindau syndrome in two pedigrees.

Qi XP, Liu WT, Li JY, Dai Y, Ma JM, Zhao Y, Fei J, Li F, Shen M, Jin HY, Chen ZG, Du ZF, Chen XL, Zhang XN.

Mol Med Rep. 2013 Sep;8(3):799-805. doi: 10.3892/mmr.2013.1578. Epub 2013 Jul 9.

PubMed [citation]

PMID:: 23842656

Genotype-phenotype correlations in Chinese von Hippel-Lindau disease patients.

Peng S, Shepard MJ, Wang J, Li T, Ning X, Cai L, Zhuang Z, Gong K.

Oncotarget. 2017 Jun 13;8(24):38456-38465. doi: 10.18632/oncotarget.16594.

PubMed [citation]

PMID:: 28388566
PMCID:: PMC5503545

See all PubMed Citations (18)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	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	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From Counsyl, SCV000785647.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442590.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: VHL c.233A>G (p.Asn78Ser) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta domain (IPR024053) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 230680 control chromosomes (gnomAD). c.233A>G has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome and has been shown to co-segregate with disease in different families (e.g. Zbar_1996, Cybulski_2002, Dollfus_2002, Huang_2004). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant impairs protein function and stability and results in compromised tight junction formation, disorganized cell morphology and increased HIF (hypoxia-inducible factor) activation (e.g. Bangiyeva_2009, Bond_2011). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as 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

From Clinical Genomics Labs, University Health Network, SCV001950147.1

#	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, SCV005187307.1

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

Description

The variant NM_000551.4(VHL):c.233A>G (p.Asn78Ser) is a missense variant predicted to cause substitution of Asparagine by Serine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 16 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 15.25, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:728151; 23842656; 25952756; 21463266; 25078357; 8634692; 23407287; 8707293; 8730290; 18067796; 12114495; 12202531; 17024664; 28388566; 18446368; 10567493; 29294023; 11850829) This variant has been identified as a de novo occurrence with unconfirmed parental relationships in 1 individual with VHL (PMID:12114495) (PM6). This variant is also seen 4 times in cancerhotspots.org, which meets the criteria of PM1_Supporting, when using somatic data to inform a germline variant curation. However, as the variant resides in the first Beta domain of VHL, a critical functional domain, it meets the full moderate criteria of (PM1). Functional data shows this variant did not alter expression of HIF1a (102% for HIF1α , similar to the truncating control used) and 86% expression for HIF2α (PS3_Supporting; PMID:21715564). The computational predictor REVEL gives a score of 0.767, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Pathogenic 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 13, 2024

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