3-10146618-G-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.445G>T(p.Ala149Ser) variant causes a missense change involving the alteration of a 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A149P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.68

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr3-10146618-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 223214.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 3-10146618-G-T is Pathogenic according to our data. Variant chr3-10146618-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 127829.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.445G>T	p.Ala149Ser	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3169G>T		intron_variant
VHL	NM_198156.3	c.341-3169G>T		intron_variant
VHL	NR_176335.1	n.774G>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.445G>T	p.Ala149Ser	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

Submissions summary: Pathogenic:5

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	Jan 03, 2019	Variant summary: VHL c.445G>T (p.Ala149Ser) results in a conservative amino acid change located in the alpha domain (IPR024048) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246270 control chromosomes (gnomAD). c.445G>T has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Mete_2014, Atuk_1998). These data indicate that the variant is very likely to be associated with disease. Functional studies also show that the variant of interest impairs wild-type function (Yang_2013). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2020

This sequence change replaces alanine with serine at codon 149 of the VHL protein (p.Ala149Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. For these reasons, this variant has been classified as Pathogenic. 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. This variant has been observed in individual(s) with von Hippel-Lindau (VHL) syndrome (PMID: 9435426, 23673869). It has also been observed to segregate with disease in related individuals. This variant is also known as c.658G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 127829). This variant is not present in population databases (ExAC no frequency). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 21, 2013

This pathogenic variant is denoted VHL c.445G>T at the cDNA level, p.Ala149Ser (A149S) at the protein level, and results in the change of an Alanine to a Serine (GCC>TCC). This variant, previously called VHL 658G>T, has been reported in two large kindreds. Atuk et. al (1998) studied an American family with over 25 cases of Von Hippel-Lindau (VHL) disease type 2A in whom the mutation demonstrated complete segregation in the 10 affected and informative unaffected individuals who were tested. In addition, Mete et al. (2013) identified the mutation in a large Turkish kindred with VHL Type 2B. Although the mutation showed incomplete segregation - present in all 11 affected family members but also in 7 unaffected family members - all but one of the unaffected carriers were in the youngest generation and possibly not old enough to show signs of disease. In sum, the family studies support pathogenicity of this variant.VHL Ala149Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This variant is a non-conservative substitution of a neutral non-polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is located in the CCT binding domain. Multiple in silico algorithms predict that this mutation may be damaging to protein structure and function. Based on the currently available information, we consider VHL Ala149Ser to be a pathogenic variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2015

The p.A149S pathogenic mutation (also known as c.445G>T), located in coding exon 2 of the VHL gene, results from a G to T substitution at nucleotide position 445. The alanine at codon 149 is replaced by serine, an amino acid with similar properties. In one study, this alteration displayed good segregation with disease in a total of 7 individuals from a large family with 25 cases of clinically confirmed von Hippel-Lindau disease (VHLD) type 2A. In this family, symptoms of pheochromocytoma developed on average at 12.5 years, and definitive diagnoses occurred on average at 19.9 years. Of note, this alteration is referred to as c.658G>T in this paper (Atuk NO, et al. J. Clin. Endocrinol. Metab. 1998;83(1):117-20). This mutation was found in another large Turkish family with VHLD type 2B and displayed good segregation with disease in a total of 9 individuals from this kindred (Mete T, et al. Endocrine 2014;45(1):128-35). In addition, one in vitro functional study showed that the half life of the protein created by this variant was much shorter, 0.6 hours, when compared to that of wild type protein, 3.8 hours. In addition, this alteration displayed decreased physical interaction with two chaperonin proteins when compared to wild type interactions, suggesting potential abnormalities in chaperonin binding possibly contributing to rapid degradation (Yang C, et al. Cell Rep 2013;3(1):52-9). Based on the supporting evidence, p.A149S is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.90
Sift4G	Uncertain	0.015	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.94		Loss of sheet (P = 0.0104);
MVP		1.0
MPC		1.0
ClinPred		0.97	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs587780077; hg19: chr3-10188302;