VHL p.Pro81Ser

Variant names:

• chr3-10142088-C-T
• rs104893829
• NM_000551.4:c.241C>T
• VHL p.Pro81Ser

Your query was ambiguous. Multiple possible variants found:

• chr3-10142088-C-T
• chr3-10142088-CCG-TCA
• chr3-10142088-CCG-TCC
• chr3-10142088-CCG-TCT
• chr3-10142088-CCG-AGC
• chr3-10142088-CCG-AGT

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM1PM5PP3BP6_Very_Strong

The NM_000551.4(VHL):c.241C>T (p.Pro81Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000353 (AC=566) in the gnomAD database across 1,605,226 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.000534. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.P81L: Pathogenic/Likely_pathogenic (ClinVar VariationId 36899, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P81A: Uncertain_significance (ClinVar VariationId 1068142, 1 star); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 3468038, 2 stars); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 2927601, 2 stars); p.P81= (synonymous): Benign (ClinVar VariationId 4071324, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Von hippel-lindau syndrome (vhl); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:12 B:15
• Conservation: PhyloP100: 1.47
• Publications: 51 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 39 pathogenic, 6 benign (OR vs. background: 30.4).
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.P81L: Pathogenic/Likely_pathogenic (ClinVar VariationId 36899, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.P81A: Uncertain_significance (ClinVar VariationId 1068142, 1 star); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 3468038, 2 stars); p.P81= (synonymous): Benign/Likely_benign (ClinVar VariationId 2927601, 2 stars); p.P81= (synonymous): Benign (ClinVar VariationId 4071324, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar germline classification: Benign/Likely Benign, 3 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL NM_000551.4	MANE Select	c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.241C>T p.Pro81Ser	missense	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 2

missense

Prot: NP_937799.1UniProt: P40337-2A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL ENST00000256474.3	TSL:1MANE Select	c.241C>T p.Pro81Ser	missense	Exon 1 of 3	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.241C>T p.Pro81Ser	missense	Exon 1 of 2	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.287C>T	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 3

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.241C>Tp.Pro81Ser

Exon rankExon 1 of 2

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.287C>T

Exon rankExon 1 of 3

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000348	AC:53	Hom:0	AN:152206	Cov:33
GnomAD2 exomes	AF: 0.000200	AC:46	Hom:	AN:230188	Cov:
GnomAD4 exome	AF: 0.000353	AC:513	Hom:1	AN:1453020	Cov:32
GnomAD4 genome	AF: 0.000348	AC:53	Hom:0	AN:152206	Cov:33
TOPMed (Bravo)	AF: 0.000348	AC:92	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000598	AC:140	Hom:0	AN:233924	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.000390	AC:5	Hom:	AN:12808	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000834 *	8	9598	0.000576 *	6	10410
BipEx(Bipolar disorder (including schizoaffective))	0.000598	17	28420	0.000381	11	28844
Epi25(Epilepsy)	0.000286	12	41958	0.000449	30	66888
SCHEMA(Schizophrenia)	0.000148	18	121784	0.000200	38	190432

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	5	7	Von Hippel-Lindau syndrome (13)
-	2	5	not provided (7)
-	2	1	not specified (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	1	-	Chuvash polycythemia (1)
1	-	-	Enchondromatosis (1)
-	1	-	Hepatoblastoma (1)
-	-	1	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.87	D
FuncVEP CTI	Pathogenic	0.71
GPN-Star LLR	N/A	-7.0
GPN-Star score	N/A	7.0
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Pathogenic	0.99	D
Mutation Taster	N/A	7/93	disease causing
MutationAssessor	Benign	1.7	L
PhyloP100	Benign	1.5
popEVE	Benign	-3.2
PrimateAI	Pathogenic	0.88	D
PromoterAI	N/A	-0.042	Neutral
PROVEAN	Uncertain	-3.2	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.68
Sift	Benign	0.038	D
Sift4G	Benign	0.39	T
Varity_R	N/A	0.81
VESM-3B	Benign	-5.7

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs104893829;

hg19: chr3-10183772;

COSMIC: COSV56546019;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar