3-10142139-T-C

Position:

• chr3-10142139-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 ENST00000256474.3(VHL):​c.292T>C​(p.Tyr98His) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,447,832 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y98S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 5.03

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 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 14 uncertain in ENST00000256474.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10142140-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 219160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 3-10142139-T-C is Pathogenic according to our data. Variant chr3-10142139-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142139-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.292T>C	p.Tyr98His	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.292T>C	p.Tyr98His	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.292T>C	p.Tyr98His	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.362T>C		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.292T>C	p.Tyr98His	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000134 AC: 3 AN: 223372 Hom.: 0 AF XY: 0.0000240 AC XY: 3 AN XY: 124746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000199

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447832 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 720736

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 21, 2023	Variant summary: VHL c.292T>C (p.Tyr98His) results in a conservative amino acid change located in the VHL beta/alpha domain (IPR022772) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 223464 control chromosomes in gnomAD. c.292T>C has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome, has been shown to segregate with disease, and has been considered a founder mutation in Black Forest region of Germany (example: Brauch_1995). At least one publication reports experimental evidence evaluating an impact on protein function. One of the most pronounced variant effects results in impaired binding with HIF protein (example: Couve_2014). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 7759077, 25371412). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all submitters have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 03, 2019	The p.Tyr98His variant in VHL has been reported in >25 individuals with Von Hippel-Lindau disease and segregated with disease in >50 affected individuals from several families, and is considered a founder variant in the Black Forest region in Germany (Bender 2001). It has also been identified in 2/100722 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 2223). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function (Hoffman 2001, Clifford 2001, Shmueli 2013). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Von Hippel- Lindeau disease. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PS3_Supporting, PP3. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 31, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 31, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11483638, 7759077, 34416425, 32869749, 31538058]. Functional studies indicate this variant impacts protein function [PMID: 28052007, 19602254, 16261165, 23840444, 11331612]. This variant is expected to disrupt protein structure [internal Myriad data]. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	May 24, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 15, 2019	This variant has been reported as pathogenic in multiple individuals and families with Von Hippel-Lindau disease in the published literature, where it has been shown to segregate with disease (PMIDs: 21204227 (2011), 19763184 (2009), 19336503 (2009), 11709017 (2001), 11483638 (2001), 10567493 (1999), 10408776 (1999), and 7759077 (1995)). Multiple experimental studies indicate that the variant is damaging to VHL protein function (PMIDs: 28643803 (2017), 20855504 (2010), 20388653 (2010), 19620968 (2009), and 16261165 (2006)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Damaging to protein function(s) relevant to disease mechanism. Moderate co-segregation with disease. However, available data are from a single family. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

VHL-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

The VHL c.292T>C variant is predicted to result in the amino acid substitution p.Tyr98His. This variant has previously been reported in multiple individuals with pheochromocytoma and Von Hippel-Lindau disease (Crossey et al. 1994. PubMed ID: 7987306, described as 505T>C/169Tyr>His; Boedeker et al. 2009. PubMed ID: 19336503; Gallou et al. 1999. PubMed ID: 10408776; Nielsen et al. 2011. PubMed ID: 21204227). This variant is reported in 3 of ~233,000 alleles in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/103904398/). This variant is interpreted as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 98 of the VHL protein (p.Tyr98His). This variant is present in population databases (rs5030809, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of VHL-related conditions (PMID: 7728151, 7759077, 10408776, 11483638, 19336503, 19763184, 21204227). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2223). 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: 10878807, 11331612, 11331613, 12510195, 16261165, 23840444, 25371412). 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

Jun 17, 2024

The p.Y98H pathogenic mutation (also known as c.292T>C), located in coding exon 1 of the VHL gene, results from a T to C substitution at nucleotide position 292. The tyrosine at codon 98 is replaced by histidine, an amino acid with similar properties. This mutation has been reported in numerous VHL families in the literature (Crossey PA et al. Hum Mol Genet. 1994 Aug;3:1303-8; Neumann HP et al. N Engl J Med. 2002 May;346:1459-66; Gallou C et al. Hum. Mutat. 2004 Sep;24:215-24; Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun;94:1938-44; Erlic Z et al. Endocr Relat Cancer. 2010 Dec;17:875-83; Nielsen SM et al. Am J Med Genet A. 2011 Jan;155A:168-73; Klingler JH et al. J Stroke Cerebrovasc Dis. 2013 May;22:437-43; Huang KL et al. Cell. 2018 04;173:355-370.e14; Liu P et al. Gland Surg, 2019 Aug;8:343-353). In addition, this mutation was shown to disrupt microtubule stabilization in vitro and has been noted to be associated with Type 2A VHL (Hergovich A et al. Nat Cell Biol. 2003;5(1):64-70; Bangiyeva V et al. BMC Cancer. 2009;9:229). Of note, this may be referred to as c.505T>A in some literature. Based on available evidence to date, this alteration is considered to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.22	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.88
Sift	Benign	0.043	.;D
Sift4G	Pathogenic	0.0	D;T
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.86		Loss of glycosylation at P103 (P = 0.0211);Loss of glycosylation at P103 (P = 0.0211);
MVP		1.0
MPC		1.2
ClinPred		0.97	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.91
gMVP		0.99

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: rs5030809; hg19: chr3-10183823;