NM_000551.4(VHL):c.241C>T (p.Pro81Ser) AND Von Hippel-Lindau syndrome

Germline classification:: Benign (11 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:: RCV000002321.36

Allele description [Variation Report for NM_000551.4(VHL):c.241C>T (p.Pro81Ser)]

NM_000551.4(VHL):c.241C>T (p.Pro81Ser)

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.241C>T (p.Pro81Ser)

Other names:

p.P81S:CCG>TCG; NM_000551.4(VHL):c.241C>T

HGVS:

NC_000003.12:g.10142088C>T
NG_008212.3:g.5454C>T
NM_000551.4:c.241C>TMANE SELECT
NM_001354723.2:c.241C>T
NM_198156.3:c.241C>T
NP_000542.1:p.Pro81Ser
NP_000542.1:p.Pro81Ser
NP_001341652.1:p.Pro81Ser
NP_937799.1:p.Pro81Ser
LRG_322t1:c.241C>T
LRG_322:g.5454C>T
LRG_322p1:p.Pro81Ser
NC_000003.11:g.10183772C>T
NM_000551.2:c.241C>T
NM_000551.3:c.241C>T
P40337:p.Pro81Ser
p.P81S
p.[Pro81Ser]

Protein change:

P81S; PRO81SER

Links:

UniProtKB: P40337#VAR_005689; OMIM: 608537.0020; dbSNP: rs104893829

NCBI 1000 Genomes Browser:

rs104893829

Molecular consequence:

NM_000551.4:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.241C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

109

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
SCV000022479	OMIM	no assertion criteria provided	Pathogenic (Nov 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000053257	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	no assertion criteria provided	Likely benign (Oct 2, 2015)	germline	clinical testing
SCV000190677	CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation	criteria provided, single submitter (Amendola et al. (Genome Res. 2015))	Likely benign (Oct 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV000264680	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Uncertain significance (Feb 26, 2016)	germline	clinical testing
SCV000890934	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jul 11, 2023)	germline	clinical testing	Citation Link,
SCV001136311	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001311112	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 27, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 23990666, 8956040, 23990664, 10761708, 19906784, 8707293, 9829911, 22234250, 11106358, 12414898 Citation Link,
SCV001950150	Clinical Genomics Labs, University Health Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 8, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175351	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Aug 29, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 8707293, 9829911, 10567493, 11106358, 19228690, 19906784, 22234250, 28503092, 25741868
SCV004841639	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]
SCV005187310	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	109	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

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response.

Desimone MC, Rathmell WK, Threadgill DW.

J Natl Cancer Inst. 2013 Sep 18;105(18):1355-64. doi: 10.1093/jnci/djt226. Epub 2013 Aug 29.

PubMed [citation]

PMID:: 23990666
PMCID:: PMC3776265

See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000022479.2

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

Description

In 6 members of a German family in which the L188V mutation in the VHL gene (608537.0014) had previously been identified in association with von Hippel-Lindau syndrome type 2C (VHLS; 193300), Weirich et al. (2002) identified a 454C-T transition in exon 1 of the VHL gene, resulting in a pro81-to-ser (P81S) mutation. The concurrent P81S mutation was identified by novel screening approaches, including denaturing high-performance liquid chromatography (DHPLC) and sequencing. The 2 mutations cosegregated with the syndrome. Weirich et al. (2002) discussed the possible impact of the mutations on protein function and phenotype.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	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, SCV000053257.2

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CSER _CC_NCGL, University of Washington - CSER - NEXT Medicine variant annotation, SCV000190677.2

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

Description

Found in patient having exome sequencing for an unrelated indication. No known history of von Hippel-Lindau syndrome. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264680.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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	unknown	not provided	not provided	not provided		3	not provided	not provided	not provided

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV000890934.4

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

Description

The VHL c.241C>T (p.Pro81Ser) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The variant is located in a mutational hotspot (COSMIC database). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies have shown mixed effects. Some functional studies have concluded that the variant behaves similar to the wild-type (Knauth 2009), whereas others suggest this variant may lead to reduced DNA damage response and resistance to ionizing radiation induced apoptosis (Li 2002, Desimone 2013). The Pro81Ser change has been reported in several individuals and families with Von Hippel Lindau-related cancers (Glavac 1996, Stolle 1998, Glasker 1999, Hes 2000, Weirich 2002, Erlic 2010, Haitz 2015, Alosi 2017). The Pro81Ser variant did not segregate with disease in a family with Von Hippel Lindau (Erlic 2009). In another family with several affected individuals, the variant was found to co-segregate in cis with another missense change in VHL (Weirich 2002). Since supporting evidence is conflicting, the clinical significance of this alteration remains unclear. It has therefore been classified as of uncertain significance.

#	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 Mendelics, SCV001136311.1

#	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 Illumina Laboratory Services, Illumina, SCV001311112.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	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, SCV001950150.1

#	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 Genetics and Molecular Pathology, SA Pathology, SCV004175351.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The VHL c.241C>T variant is a single nucleotide change in exon 1/3 of the VHL gene, which is predicted to change the amino acid proline at position 81 in the protein to serine. This variant is situated at the alpha-beta domain interface (PM1). The population frequency is higher than expected for a disease-causing VHL variant (gnomAD 0.035%, 53/152206) (PM2 Not Met). This variant has been reported in several families and individuals with VHL-related syndromes, including RCC, hemangioblastoma, and paraganglioma (PMID: 28503092, 8707293, 9829911, 10567493, 11106358) (PS4). Erlic et al. (PMID: 19906784) reported an affected individual who had inherited this variant from his unaffected father, but who also had an in trans, de novo deletion of the entire VHL gene (BP2). Alosi et al. (PMID: 28503092) reported a kindred with 5 carriers of the variant and only one family member was affected with early onset renal clear cell cancer, suggesting that suggesting that the variant does not segregate with disease (BS4) or it may be a variant of variable penetrance. In silico tools suggest the impact of the variant on protein function is inconclusive. Functional studies have shown activity close to wildtype (PMID: 19228690), or a slight reduction to target protein binding with minimal impact to the protein complex functionality, except when in conjunction with another VHL variant (PMID: 22234250). The variant has been reported in dbSNP (rs104893829) and HGMD (CM951274). The variant has been reported with conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID:2233).

#	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		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004841639.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	106	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		106	not provided	not provided	not provided

From ClinGen VHL Variant Curation Expert Panel, ClinGen, SCV005187310.1

#	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.241C>T (p.Pro81Ser) is a missense variant in the first exon of the VHL gene. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0004281 (543/1179690 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). Therefore this variant meets the criterion for (BA1) and is classified as Benign for autosomal-dominant von Hippel-Lindau disease (VHL disease) 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: Nov 3, 2024

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