rs869025633

Variant names:

• chr3-10142182-A-C
• rs869025633
• NM_000551.4:c.335A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10142182-A-C
• chr3-10142182-A-G
• chr3-10142182-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_000551.4(VHL):​c.335A>C​(p.Tyr112Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y112C) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.09
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 31 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 20 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 chr3-10142182-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 223189.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 3-10142182-A-C is Pathogenic according to our data. Variant chr3-10142182-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1730577.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.335A>C	p.Tyr112Ser	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.335A>C	p.Tyr112Ser	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.335A>C	p.Tyr112Ser	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.405A>C		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.335A>C	p.Tyr112Ser	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Oct 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 112 of the VHL protein (p.Tyr112Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (internal data). ClinVar contains an entry for this variant (Variation ID: 1730577). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. This variant disrupts the p.Tyr112 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 8863170, 10533030, 11331613, 15574766, 19030229, 19602254, 21204227, 24002598). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 07, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y112S variant (also known as c.335A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 335. The tyrosine at codon 112 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		4.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0090	.;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.87		Gain of disorder (P = 0.0064);Gain of disorder (P = 0.0064);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		-0.070	Neutral
Varity_R		0.92
gMVP		0.98
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs869025633; hg19: chr3-10183866;