NM_000551.4(VHL):c.445G>T (p.Ala149Ser) AND Von Hippel-Lindau syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 3, 2019
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000208783.2

Allele description [Variation Report for NM_000551.4(VHL):c.445G>T (p.Ala149Ser)]

NM_000551.4(VHL):c.445G>T (p.Ala149Ser)

Genes:

LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [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.445G>T (p.Ala149Ser)

Other names:

p.A149S:GCC>TCC

HGVS:

NC_000003.12:g.10146618G>T
NG_008212.3:g.9984G>T
NG_046756.1:g.4380G>T
NM_000551.4:c.445G>TMANE SELECT
NM_001354723.2:c.*18-3169G>T
NM_198156.3:c.341-3169G>T
NP_000542.1:p.Ala149Ser
NP_000542.1:p.Ala149Ser
LRG_322t1:c.445G>T
LRG_322:g.9984G>T
LRG_322p1:p.Ala149Ser
NC_000003.11:g.10188302G>T
NM_000551.3:c.445G>T
p.[Ala149Ser]

Protein change:

A149S

Links:

dbSNP: rs587780077

NCBI 1000 Genomes Browser:

rs587780077

Molecular consequence:

NM_001354723.2:c.*18-3169G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3169G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.445G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Von Hippel-Lindau syndrome (VHLS)
Synonyms:: VHL syndrome; Von Hippel-Lindau
Identifiers:: MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264741	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Pathogenic (Feb 26, 2016)	germline	clinical testing
SCV000697515	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 3, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9435426, 23318261, 23673869 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000264741

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

no assertion criteria provided

Pathogenic
(Feb 26, 2016)

germline

clinical testing

SCV000697515

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 3, 2019)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	8	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Pheochromocytoma in von Hippel-Lindau disease: clinical presentation and mutation analysis in a large, multigenerational kindred.

Atuk NO, Stolle C, Owen JA Jr, Carpenter JT, Vance ML.

J Clin Endocrinol Metab. 1998 Jan;83(1):117-20. Erratum in: J Clin Endorcinol Metab 1998 Apr;83(4):1150.

PubMed [citation]

PMID:: 9435426

Proteostasis modulators prolong missense VHL protein activity and halt tumor progression.

Yang C, Huntoon K, Ksendzovsky A, Zhuang Z, Lonser RR.

Cell Rep. 2013 Jan 31;3(1):52-9. doi: 10.1016/j.celrep.2012.12.007. Epub 2013 Jan 10.

PubMed [citation]

PMID:: 23318261
PMCID:: PMC3563731

See all PubMed Citations (3)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264741.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		8	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697515.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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.

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

Last Updated: May 1, 2024

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