NM_016204.4(GDF2):c.1267G>A (p.Val423Met) AND Telangiectasia, hereditary hemorrhagic, type 5

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 9, 2023
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:: RCV000651839.6

Allele description [Variation Report for NM_016204.4(GDF2):c.1267G>A (p.Val423Met)]

NM_016204.4(GDF2):c.1267G>A (p.Val423Met)

Gene:

GDF2:growth differentiation factor 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q11.22

Genomic location:

Preferred name:

NM_016204.4(GDF2):c.1267G>A (p.Val423Met)

HGVS:

NC_000010.11:g.47325761G>A
NG_033916.1:g.8272G>A
NM_016204.4:c.1267G>AMANE SELECT
NP_057288.1:p.Val423Met
NC_000010.10:g.48413601C>T
NM_016204.2:c.1267G>A

Protein change:

V423M

Links:

dbSNP: rs1358534877

NCBI 1000 Genomes Browser:

rs1358534877

Molecular consequence:

NM_016204.4:c.1267G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Telangiectasia, hereditary hemorrhagic, type 5 (HHT5)
Identifiers:: MONDO: MONDO:0014217; MedGen: C3809710; Orphanet: 774; OMIM: 615506

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000773695	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 9, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31727138, 30578397, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000773695

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 9, 2023)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Novel risk genes and mechanisms implicated by exome sequencing of 2572 individuals with pulmonary arterial hypertension.

Zhu N, Pauciulo MW, Welch CL, Lutz KA, Coleman AW, Gonzaga-Jauregui C, Wang J, Grimes JM, Martin LJ, He H; PAH Biobank Enrolling Centers’ Investigators., Shen Y, Chung WK, Nichols WC.

Genome Med. 2019 Nov 14;11(1):69. doi: 10.1186/s13073-019-0685-z. Erratum in: Genome Med. 2022 Feb 7;14(1):12.

PubMed [citation]

PMID:: 31727138
PMCID:: PMC6857288

Germline BMP9 mutation causes idiopathic pulmonary arterial hypertension.

Wang XJ, Lian TY, Jiang X, Liu SF, Li SQ, Jiang R, Wu WH, Ye J, Cheng CY, Du Y, Xu XQ, Wu Y, Peng FH, Sun K, Mao YM, Yu H, Liang C, Shyy JY, Zhang SY, Zhang X, Jing ZC.

Eur Respir J. 2019 Mar 14;53(3). doi:pii: 1801609. 10.1183/13993003.01609-2018. Print 2019 Mar.

PubMed [citation]

PMID:: 30578397

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000773695.4

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

Description

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 423 of the GDF2 protein (p.Val423Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with pulmonary arterial hypertension (PMID: 30578397, 31727138). ClinVar contains an entry for this variant (Variation ID: 541539). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GDF2 function (PMID: 30578397). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Feb 20, 2024

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