rs1553619424

Positions:

• chr3-10142087-T-A
• chr3-10142087-T-C
• chr3-10142087-T-G

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.240T>A​(p.Ser80Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S80N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0280

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 22 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 3-10142087-T-A is Pathogenic according to our data. Variant chr3-10142087-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3148494.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.240T>A	p.Ser80Arg	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.240T>A	p.Ser80Arg	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.240T>A	p.Ser80Arg	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.310T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.240T>A	p.Ser80Arg	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 24, 2024

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 19755989, 12624160, 33720516, 12202531, 20978319, 8956040, 29748190]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2023

The p.S80R variant (also known as c.240T>A), located in coding exon 1 of the VHL gene, results from a T to A substitution at nucleotide position 240. The serine at codon 80 is replaced by arginine, an amino acid with dissimilar properties. Other alterations at the same codon, including p.S80R (c.240T>G) and p.S80G (c.238A>G), have been described in multiple individual with a personal and/or family history that is consistent with VHL-related disease (Crossey PA et al. Hum Mol Genet, 1994 Aug;3:1303-8; Woodward ER et al. Hum Mol Genet. 1997 Jul;6(7):1051-6; Assadi F & Brackbill EL. Am J Kidney Dis. 2003 Jan;41(1):E3; Erlic Z et al. Endocr Relat Cancer, 2010 Dec;17:875-83; Krauss T et al. Endocr Relat Cancer, 2018 Sep;25:783-793). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Benign	0.044
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.80		Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-10183771; COSMIC: COSV56542846; COSMIC: COSV56542846;