rs786202787

Positions:

• chr3-10142085-A-C
• chr3-10142085-A-G
• chr3-10142085-A-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000551.4(VHL):​c.238A>C​(p.Ser80Arg) 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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S80N) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.72

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 16 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• PP5: Variant 3-10142085-A-C is Pathogenic according to our data. Variant chr3-10142085-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 496052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.238A>C	p.Ser80Arg	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.238A>C	p.Ser80Arg	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.238A>C	p.Ser80Arg	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.308A>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.238A>C	p.Ser80Arg	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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: The c.238A>C variant affects a conserved nucleotide, resulting in amino acid change from Ser to Arg. 4/4 in-silico tools predict damaging outcome for this variant. This variant has been reported in mutlitple VHL patients, including 10 affected members in one family. The variant is not found in 95076 control chromosomes. In addition, one reputable database classified this variant as "mutation". Amino acid changes at Ser80 (Ser80Gly, Ser80Ile, Ser80Asn) have been classified as pathogenic/likely pathogenic. Taken together, this variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.3	D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	D;D
Vest4		0.62
MutPred		0.80		Gain of MoRF binding (P = 0.0298);Gain of MoRF binding (P = 0.0298);
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		1.0

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: rs786202787; hg19: chr3-10183769; COSMIC: COSV56547599; COSMIC: COSV56547599;