3-10142092-G-T

Variant names:

• chr3-10142092-G-T
• rs794726890
• NM_000551.4:c.245G>T

Variant summary

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

The NM_000551.4(VHL):​c.245G>T​(p.Arg82Leu) 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. R82P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.04

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 chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142092-G-C is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-10142092-G-T is Pathogenic according to our data. Variant chr3-10142092-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.245G>T	p.Arg82Leu	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.245G>T	p.Arg82Leu	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.245G>T	p.Arg82Leu	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.315G>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.245G>T	p.Arg82Leu	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1452188 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722708

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Mar 03, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23626751, 30877234, 23327821, 34036514]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Jul 08, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: VHL c.245G>T (p.Arg82Leu) results in a non-conservative amino acid change located in the VHL disease tumor suppressor, beta/alpha domain (IPR022772) 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 229092 control chromosomes. c.245G>T has been reported in the literature in the setting of bilateral pheochromocytoma in the absence of other tumors reported in patients with von Hippel-Lindau disease (example, Mary John_2013, Amini_2013) and a in report of custom multigene panel of 17 paraganglioma and pheochromocytoma (PPGL) genes (Ben Amin_2019). The variant segregated with bilateral pheochromocytoma in one family (Mary John_2013) and originated de-novo in the other (Amini_2013). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Although several reports describing an impact of a different missense variant located at this codon, namely p.Arg82Pro as impacting VHL function have been published, supporting the relevance of this Arginine residue. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic citing overlapping clinical evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

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

Aug 17, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A different missense substitution at this codon (p.Arg82Pro) has been reported to segregate with von Hippel-Lindau syndrome in two families (PMID: 12603429, 20447124). Experimental studies have shown that this missense change disrupts the normal function of VHL protein (PMID: 26973240, 11739384, 10823831). This suggests that the arginine residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to be de novo in an individual affected with bilateral adrenal pheochromocytoma (PMID: 23327821). In addition, this variant has been reported to segregate with bilateral pheochromocytoma in one family (PMID: 23626751). This sequence change replaces arginine with leucine at codon 82 of the VHL protein (p.Arg82Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 10, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R82L variant (also known as c.245G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 245. The arginine at codon 82 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with VHL spectrum tumors, including a proband and two children all with bilateral pheochromocytomas and all positive for this variant (Amini Z et al. J. Pediatr. Endocrinol. Metab., 2013;26:369-72; Krauss T et al. Endocr. Relat. Cancer, 2018 09;25:783-793; Ebenazer A et al. Fam. Cancer, 2013 Sep;12:519-24; John AM et al. PLoS ONE, 2013 Apr;8:e61908; Penitenti F et al. Endocrine, 2021 Oct;74:180-187; Ambry internal data). Based on internal structural analysis, R82L is deleterious (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.96
Sift	Benign	0.17	.;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.90		Loss of MoRF binding (P = 0.013);Loss of MoRF binding (P = 0.013);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.99

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: rs794726890; hg19: chr3-10183776; COSMIC: COSV56545575; COSMIC: COSV56545575;