NM_000551.4(VHL):c.222C>A (p.Val74=) AND Chuvash polycythemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 9, 2021
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000984026.4

Allele description [Variation Report for NM_000551.4(VHL):c.222C>A (p.Val74=)]

NM_000551.4(VHL):c.222C>A (p.Val74=)

Gene:

VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.222C>A (p.Val74=)

Other names:

V75V

HGVS:

NC_000003.12:g.10142069C>A
NG_008212.3:g.5435C>A
NM_000551.4:c.222C>AMANE SELECT
NM_001354723.2:c.222C>A
NM_198156.3:c.222C>A
NP_000542.1:p.Val74=
NP_000542.1:p.Val74=
NP_001341652.1:p.Val74=
NP_937799.1:p.Val74=
LRG_322t1:c.222C>A
LRG_322:g.5435C>A
LRG_322p1:p.Val74=
NC_000003.11:g.10183753C>A
NM_000551.3:c.222C>A

Protein change:

VAL75VAL

Links:

OMIM: 608537.0034; dbSNP: rs759737367

NCBI 1000 Genomes Browser:

rs759737367

Molecular consequence:

NM_000551.4:c.222C>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001354723.2:c.222C>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_198156.3:c.222C>A - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

cryptic splice donor activation [Variation Ontology: 0374]

Condition(s)

Name:: Chuvash polycythemia
Synonyms:: POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
Identifiers:: MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000924583	Cellular and Molecular Biology Laboratory, University of Campania Luigi Vanvitelli	no assertion criteria provided	Pathogenic (Jun 21, 2019)	not applicable	in vitro, in vivo
SCV001167317	OMIM	no assertion criteria provided	Pathogenic (Feb 9, 2021)	germline	literature only	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000924583

Cellular and Molecular Biology Laboratory, University of Campania Luigi Vanvitelli

no assertion criteria provided

Pathogenic
(Jun 21, 2019)

not applicable

in vitro, in vivo

SCV001167317

OMIM

no assertion criteria provided

Pathogenic
(Feb 9, 2021)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro, in vivo

Citations

PubMed

Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria.

Perrotta S, Roberti D, Bencivenga D, Corsetto P, O'Brien KA, Caiazza M, Stampone E, Allison L, Fleck RA, Scianguetta S, Tartaglione I, Robbins PA, Casale M, West JA, Franzini-Armstrong C, Griffin JL, Rizzo AM, Sinisi AA, Murray AJ, Borriello A, Formenti F, Della Ragione F.

N Engl J Med. 2020 Feb 27;382(9):835-844. doi: 10.1056/NEJMoa1907362.

PubMed [citation]

PMID:: 32101665

Details of each submission

From Cellular and Molecular Biology Laboratory, University of Campania Luigi Vanvitelli, SCV000924583.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	not provided
2	not provided	not provided	not provided	not provided	in vitro	not provided
3	not provided	not provided	not provided	not provided	in vivo	not provided

Description

This mutation has been reported in a kindred of related Italian parents. The patient has been affected with an early systemic onset of the disease and showed, on top of the erythrocytosis, strongly reduced growth rate, persistent hypoglycemia and limited exercise capacity. We highlighted changes in gene expression reprogramming carbohydrate and lipid metabolism, impairing muscle mitochondrial respiratory function and uncoupling oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided
3	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From OMIM, SCV001167317.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a 22-year-old man, born of consanguineous Italian parents, with familial erythrocytosis-2 (ECYT2; 263400), Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutation created a alternative splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls, suggesting possible mitochondrial dysfunction. The patient presented at birth with severe hypoglycemia, erythrocytosis, and bradycardia. He later showed failure to thrive, exercise intolerance, and mitochondrial and metabolic abnormalities.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 26, 2023

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