rs1060503554

chr3-10142070-A-Cchr3-10142070-A-Gchr3-10142070-A-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.223A>C(p.Ile75Leu) 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. I75S) 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: 2.49

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 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 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 chr3-10142071-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420073.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.223A>C	p.Ile75Leu	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.223A>C	p.Ile75Leu	missense_variant	1/3
VHL	NM_198156.3	c.223A>C	p.Ile75Leu	missense_variant	1/2
VHL	NR_176335.1	n.293A>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.223A>C	p.Ile75Leu	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

Oct 22, 2016

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. This sequence change replaces isoleucine with leucine at codon 75 of the VHL protein (p.Ile75Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

The p.I75L variant (also known as c.223A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 223. The isoleucine at codon 75 is replaced by leucine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6401 samples (12802 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 12000 alleles tested) in our clinical cohort. 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	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Uncertain	0.63	D;.
Eigen	Benign	0.032
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	0.79	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.70	N;N
REVEL	Uncertain	0.51
Sift4G	Benign	0.37	T;T
Polyphen		0.44	B;P
Vest4		0.33
MutPred		0.68		Gain of glycosylation at S72 (P = 0.0212);Gain of glycosylation at S72 (P = 0.0212);
MVP		1.0
MPC		0.42
ClinPred		0.75	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.95

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: rs1060503554; hg19: chr3-10183754;