rs864622267

chr3-10142154-C-Gchr3-10142154-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_000551.4(VHL):c.307C>G(p.Pro103Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P103L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.35

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain 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 chr3-10142155-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1488386.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.307C>G	p.Pro103Ala	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.307C>G	p.Pro103Ala	missense_variant	1/3
VHL	NM_198156.3	c.307C>G	p.Pro103Ala	missense_variant	1/2
VHL	NR_176335.1	n.377C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.307C>G	p.Pro103Ala	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Pro103 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 18928468, 23407919, 30877234), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 219823). This variant has been observed in individual(s) with pheocromocytoma (PMID: 21463266). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with alanine at codon 103 of the VHL protein (p.Pro103Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 2019

The p.P103A variant (also known as c.307C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 307. The proline at codon 103 is replaced by alanine, an amino acid with highly similar properties. This variant was identified in an individual with pheochromocytoma at age 16 but was classified as "nondeleterious" by authors upon performing in silico evaluation, structural assessment, and using bioinformatics approaches to predict functional impact (Leonardi E et al. Ann. Hum. Genet., 2011 Jul;75:483-96). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;.
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.67	N;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.58
Sift4G	Benign	0.085	T;T
Polyphen		0.40	B;B
Vest4		0.34
MutPred		0.73		Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);
MVP		1.0
MPC		0.32
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.94

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: rs864622267; hg19: chr3-10183838;