3-10142181-T-C

Position:

• chr3-10142181-T-C

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.334T>C​(p.Tyr112His) 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 Pathogenic (★★). 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: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.01

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 hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr3-10142181-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-10142181-T-C is Pathogenic according to our data. Variant chr3-10142181-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2222.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.334T>C	p.Tyr112His	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.334T>C	p.Tyr112His	missense_variant	1/3
VHL	NM_198156.3	c.334T>C	p.Tyr112His	missense_variant	1/2
VHL	NR_176335.1	n.404T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.334T>C	p.Tyr112His	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1996	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2018	Variant summary: VHL c.334T>C (p.Tyr112His) results in a conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, beta/alpha domain 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 217656 control chromosomes. c.334T>C has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome including a large kindred comprised of 107 people with or at-risk for VHL, of whom 49 have been diagnosed and 35/49 (71%) are clinically affected (Nielsen_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

VHL-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 05, 2023

The VHL c.334T>C variant is predicted to result in the amino acid substitution p.Tyr112His. This variant also described using legacy nomenclature as c.547T>C, p.Y111H; has been well-documented to be pathogenic for Type 2A von Hippel-Lindau disease (VHL) with pheochromocytoma (Chen et al. 1995. PubMed ID: 7728151; Zbar et al. 1996. PubMed ID: 8956040; Nielsen et al. 2011. PubMed ID: 21204227). Functional studies showed that this variant affects VHL function (Rathmell et al. 2004. PubMed ID: 15574766; Hacker et al. 2008. PubMed ID: 19030229). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 09, 2024

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 112 of the VHL protein (p.Tyr112His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pheochromocytoma in two families and has been found in an independent family affected with the same condition (PMID: 7728151, 8863170, 21204227). It has also been observed to segregate with disease in related individuals. This variant is also known as c.547T>C, p.Y111H. ClinVar contains an entry for this variant (Variation ID: 2222). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects VHL function (PMID: 15574766, 19030229, 24002598). 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: 10533030, 11331613, 19602254). 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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2021

The p.Y112H pathogenic mutation (also known as c.334T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 334. The tyrosine at codon 112 is replaced by histidine, an amino acid with similar properties. This variant has been associated with Type 2A VHL and reported to segregate with pheochromocytoma in two large families and has been found in another independent family affected with pheochromocytoma and angiomas (Tisherman SE et al. Arch Intern Med, 1993 Nov;153:2550-6; Chen F et al. Hum Mutat, 1995;5:66-75; Chen F et al. J Med Genet, 1996 Aug;33:716-7; Nielsen SM et al. Am J Med Genet A, 2011 Jan;155A:168-73). Experimental studies have shown that this alteration results in an intermediate degree of HIF regulation in VHL null murine embryonic stem cell expression system and also leads to an increased microvessel density in a mouse model for teratoma analysis (Rathmell WK et al. Cancer Res, 2004 Dec;64:8595-603; Hacker KE et al. PLoS One, 2008 Nov;3:e3801). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.86	D;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.6	D;N
REVEL	Pathogenic	0.85
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.95		Gain of disorder (P = 0.0205);Gain of disorder (P = 0.0205);
MVP		1.0
MPC		0.54
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.96

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: rs104893824; hg19: chr3-10183865;