rs398123481

Positions:

• chr3-10142103-C-G
• chr3-10142103-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000256474.3(VHL):​c.256C>G​(p.Pro86Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P86L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 13 uncertain in ENST00000256474.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142104-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 182977.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 3-10142103-C-G is Pathogenic according to our data. Variant chr3-10142103-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 93327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.256C>G	p.Pro86Ala	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.256C>G	p.Pro86Ala	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.256C>G	p.Pro86Ala	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.326C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.256C>G	p.Pro86Ala	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 29, 2016	Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic. -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2019

This sequence change replaces proline with alanine at codon 86 of the VHL protein (p.Pro86Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 17102082, 27034144, 7728151, Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.469C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 93327). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340, 11257211, 19408298). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 02, 2013

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 05, 2024

The p.P86A variant (also known as c.256C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 256. The proline at codon 86 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals with clinical findings of von Hippel Lindau (VHL) (Ambry internal data; Chen F et al. Hum Mutat, 1995;5:66-75; Castellano M et al. Ann N Y Acad Sci, 2006 Aug;1073:156-65; Ferrara AM et al. Cancer Res Treat, 2016 Oct;48:1438-1442; Reich M et al. Acta Ophthalmol, 2021 Dec;99:e1492-e1500; Morlacchi LC et al. ERJ Open Res, 2023 Nov;9:). Of note, this alteration is also known as 469C>G in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.018	.;D
Sift4G	Benign	0.066	T;D
Polyphen		1.0	D;D
Vest4		0.60
MutPred		0.96		Loss of disorder (P = 0.0328);Loss of disorder (P = 0.0328);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs398123481; hg19: chr3-10183787; COSMIC: COSV56564109; COSMIC: COSV56564109;