rs869025631

Positions:

• chr3-10142179-G-A
• chr3-10142179-G-C
• chr3-10142179-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The ENST00000256474.3(VHL):​c.332G>A​(p.Ser111Asn) 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. S111I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: VHL ENST00000256474.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.02

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 15 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr3-10142178-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 633016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81
• PP5: Variant 3-10142179-G-A is Pathogenic according to our data. Variant chr3-10142179-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 223186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142179-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.332G>A	p.Ser111Asn	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.332G>A	p.Ser111Asn	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.332G>A	p.Ser111Asn	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.402G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.332G>A	p.Ser111Asn	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446050 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 719814

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2016	Variant summary: This c.332G>A variant affects a conserved nucleotide, resulting in amino acid change from Ser to Asn. Although 4/4 in-silico tools predict this variant to be benign, no functional studies have been performed to confirm these predictions. This variant was not found in approximately 92088 control chromosomes including the broad and large populations from ExAC. In literature, the variant has been widely reported as a pathogenic variant found in several patients/families with VHL disease, including somatic occurrences. This p.Ser111 is likely to be a mutational hot-spot where other likely pathogenic variant [such as p.S111R (c.331A>C and c.333C>G), p.S111C, p.S111I, etc.] have also been reported. At least one reputable database classifies the variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 02, 2022

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 111 of the VHL protein (p.Ser111Asn). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser111 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7728151, 12114495, 16868829, 22071692, 25562111; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 223186). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 7728151, 27527340, 28849724). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2013

The p.S111N mutation (also known as c.332G>A) is located in exon 1 of the VHL gene. This alteration results from a G to A substitution at nucleotide position 332. The serine at codon 111 is replaced by asparagine, an amino acid with similar properties. This mutation has been reported in many VHL families affected with retinal angiomas, CNS hemangioblastomas, and renal cell carcinoma. None of the families in the literature had a history of pheochromocytomas which would fit the clinical description of VHL Type 1 (Chen et al. Human Mutation. 1995. 5:66-75; Maher et al. J Med Genet. 1996: 33328-332; Zbar et al. Human Mutation. 1996. 8:348-357; Ong et al. Human Mutation. 2007. 28(2):143-149; Zhang et al. J Cancer Res Clin Oncol. 2008. 134:1211-1218). Based on the available evidence, p.S111N is classified as a pathogenic mutation. This mutation has been referred to as p.S182N (c.545G>A) in older literature. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D;.
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.54
Sift	Benign	0.12	.;T
Sift4G	Benign	0.094	T;T
Polyphen		0.14	B;B
Vest4		0.86
MutPred		0.78		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		1.0
MPC		0.31
ClinPred		0.80	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
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: rs869025631; hg19: chr3-10183863; COSMIC: COSV56542714; COSMIC: COSV56542714;