rs864622646

Positions:

• chr3-10146518-C-A
• chr3-10146518-C-G
• chr3-10146518-C-T

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.345C>A​(p.His115Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H115P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0360

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, 10 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 chr3-10146517-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 560744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 3-10146518-C-A is Pathogenic according to our data. Variant chr3-10146518-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496057.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.345C>A	p.His115Gln	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3269C>A		intron_variant
VHL	NM_198156.3	c.341-3269C>A		intron_variant
VHL	NR_176335.1	n.674C>A		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.345C>A	p.His115Gln	missense_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 05, 2016

Variant summary: This c.345C>A affects a non-conserved nucleotide, resulting in amino acid change from His to Gln. 2/3 in-silico tools predict this variant to be damaging. The residue p.His115 is reported to be critical for interaction with HIF, thus this missense change is unlikely to be tolerated. By a structural/functional assay, interaction energy of residue was ~1.5 kcal/mol weaker than that with histidine in the wild type (Domene_2012), thus proving that the variant leads to functional impairment. This variant was not found in approximately 121600 control chromosomes, including the broad and large populations from ExAC. In literature, the p.His115Gln has been reported as a pathogenic variant found in >6 independent VHL patients/families, including somatic occurrences. At least one database calls this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 19, 2019

This variant has been reported to affect VHL protein function (PMID:28775317). This missense change has been observed in individuals with Von Hippel-Lindau syndrome (VHL) or clinical features of VHL (PMID: 19949673, 9829912, 7728151, 9681856, 29749453). ClinVar contains an entry for this variant (Variation ID: 496057). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 115 of the VHL protein (p.His115Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant disrupts the p.His115 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 17024664, 8707293, 22357542), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.074
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	0.82	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.85
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.96		Gain of sheet (P = 0.039);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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: rs864622646; hg19: chr3-10188202; COSMIC: COSV56545969;