3-10149856-T-C

Position:

• chr3-10149856-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.533T>C​(p.Leu178Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.26

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 96 pathogenic changes around while only 8 benign (92%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 3-10149856-T-C is Pathogenic according to our data. Variant chr3-10149856-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 428795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.533T>C	p.Leu178Pro	missense_variant	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.410T>C	p.Leu137Pro	missense_variant	2/2		NP_937799.1
VHL	NM_001354723.2	c.*87T>C		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.862T>C		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.533T>C	p.Leu178Pro	missense_variant	3/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727242

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

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	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	Jan 02, 2024	The c.533T>C (p.Leu178Pro) variant in the VHL gene is located on the exon 3 and is predicted to replace leucine with proline at codon 178 (p.Leu178Pro). The variant has been reported in multiple unrelated individuals with von Hippel–Lindau disease and/or pheochromocytoma and segregate with disease (PMID: 31383958, 25867206, 19464396, 8956040, 9452106). An alternative variant disrupting the same amino acid (p.Leu178Arg) has been reported in individuals with Von Hippel-Lindau disease and interpreted as pathogenic (ClinVar ID: 625261). The variant is reported in ClinVar (ID: 428795). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.951). Therefore, the c.533T>C (p.Leu178Pro) variant of VHL has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 08, 2024	The c.533T>C (p.Leu178Pro) variant in the VHL gene is located on the exon 3 and is predicted to replace leucine with proline at codon 178 (p.Leu178Pro). The variant has been reported in multiple unrelated individuals with von Hippel-Lindau disease and/or pheochromocytoma and segregate with disease (PMID: 31383958, 25867206, 19464396, 8956040, 9452106). An alternative variant disrupting the same amino acid (p.Leu178Arg) has been reported in individuals with Von Hippel-Lindau disease and interpreted as pathogenic (ClinVar ID: 625261). The variant is reported in ClinVar (ID: 428795). The variant is absent in the general population database (gnomAD). Computational prediction algorithms suggest a deleterious impact for this variant (REVEL score 0.951). Therefore, the c.533T>C (p.Leu178Pro) variant of VHL has been classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 25, 2022

ClinVar contains an entry for this variant (Variation ID: 428795). This variant is also known as 746T>C (p.L249P). This missense change has been observed in individuals with von Hippel-Lindau disease (PMID: 17024664, 19464396, 19763184, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 178 of the VHL protein (p.Leu178Pro). 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. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8634692, 12114495, 7987306, 33415482, 25563310, 18836774, 11058902, 19009041, 19763184, 29748190, 36316043, 35466127, 27527340, 16314641, 14722919, 8956040, 7728151, 10567493, 8707293, 17024664, 7553625, 10408776, 25867206, 19464396, 10761708, 21972040) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 29, 2022

The p.L178P pathogenic mutation (also known as c.533T>C), located in coding exon 3 of the VHL gene, results from a T to C substitution at nucleotide position 533. The leucine at codon 178 is replaced by proline, an amino acid with some similar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with Von Hippel-Lindau syndrome (VHL) both with and without pheochromocytoma (Crossey PA et al. Hum. Mol. Genet. 1994 Aug3(8):1303-8; Erlic et al. Endocrine-Related Cancer. 2010. 17;875-883; Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67(6):758-62; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zbar B et al. Hum. Mutat. 1996;8(4):348-57; Krauss T et al. Endocr Relat Cancer, 2018 09;25:783-793; Bausch B et al. Head Neck, 2016 04;38 Suppl 1:E673-9; Ciotti P et al. Eur J Med Genet May;52:311-4; Ambry internal data). This alteration has also been reported in individuals with personal history of pheochromocytoma or functional paraganglioma but without a formal diagnosis of VHL syndrome (Amar L et al. J. Clin. Oncol. 2005 Dec;23(34):8812-8). In the literature, this alteration has also been referred to as a common VHL germline mutation (Cybulski C et al. J. Med. Genet. 2002 Jul;39(7):E38; López-Guerrero JA et al. Adv Urol 2008:720840). Of note, this alteration is also designated as 746T>C in some published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.4	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.97		Loss of stability (P = 0.0086);.;
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.99
gMVP		0.97

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: rs5030822; hg19: chr3-10191540; COSMIC: COSV56547906;