rs1060503548

Variant names:

• chr3-10141909-A-C
• rs1060503548
• NM_000551.4:c.62A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10141909-A-C
• chr3-10141909-A-G
• chr3-10141909-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000551.4(VHL):​c.62A>C​(p.Glu21Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,381,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E21K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: -0.0630

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a chain von Hippel-Lindau disease tumor suppressor (size 212) in uniprot entity VHL_HUMAN there are 319 pathogenic changes around while only 73 benign (81%) in NM_000551.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.13200617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.62A>C	p.Glu21Ala	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.62A>C	p.Glu21Ala	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.62A>C	p.Glu21Ala	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.132A>C		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.62A>C	p.Glu21Ala	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 141400 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1381672 Hom.: 0 Cov.: 32 AF XY: 0.0000162 AC XY: 11 AN XY: 679226

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 30862

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 34144

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 24426

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 35332

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 77574

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48070

Gnomad4 NFE exome AF: 0.0000206 AC: 22 AN: 1070168

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 56976

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000509 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Oct 15, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The VHL c.62A>C (p.Glu21Ala) variant has been reported in the published literature in an individual with erythrocytosis (PMID: 29790589 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Apr 25, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of clear cell renal carcinoma or erythrocytosis (Pea-Llopis et al., 2012; Oliveira et al., 2018); This variant is associated with the following publications: (PMID: 22683710, 22076155, 29790589) -

Chuvash polycythemia Uncertain:1

Jul 27, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 21 of the VHL protein (p.Glu21Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with erythrocytosis or clear-cell type renal cell carcinoma (PMID: 22683710, 29790589). ClinVar contains an entry for this variant (Variation ID: 411957). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt VHL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E21A variant (also known as c.62A>C), located in coding exon 1 of the VHL gene, results from an A to C substitution at nucleotide position 62. The glutamic acid at codon 21 is replaced by alanine, an amino acid with dissimilar properties. This alteration was identified in one individual diagnosed with renal cell carcinoma (Peña-Llopis S et al. Nat. Genet. 2012 Jun;44:751-9). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	14
DANN	Benign	0.86
DEOGEN2	Benign	0.37	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.41	N
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.29
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.038	D;D
Polyphen		0.10	B;P
Vest4		0.16
MutPred		0.23		Gain of glycosylation at Y23 (P = 0.0012);Gain of glycosylation at Y23 (P = 0.0012);
MVP		0.98
MPC		0.53
ClinPred		0.23	T
GERP RS		0.32
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.093
gMVP		0.56
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503548; hg19: chr3-10183593;