NM_003238.6(TGFB2):c.958C>T (p.Arg320Cys) AND Holt-Oram syndrome

delete

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 24, 2020
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:: RCV001247561.2

Allele description

NM_003238.6(TGFB2):c.958C>T (p.Arg320Cys)

Gene:

TGFB2:transforming growth factor beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_003238.6(TGFB2):c.958C>T (p.Arg320Cys)

HGVS:

NC_000001.11:g.218437368C>T
NG_027721.2:g.97035C>T
NM_001135599.4:c.1042C>T
NM_003238.6:c.958C>TMANE SELECT
NP_001129071.1:p.Arg348Cys
NP_003229.1:p.Arg320Cys
NC_000001.10:g.218610710C>T
NM_001135599.2:c.1042C>T
NM_003238.3:c.958C>T
NR_138148.2:n.2209C>T
NR_138149.2:n.2293C>T

Protein change:

R320C; ARG348CYS

Links:

OMIM: 190220.0005; dbSNP: rs1553303352

NCBI 1000 Genomes Browser:

rs1553303352

Molecular consequence:

NM_001135599.4:c.1042C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003238.6:c.958C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_138148.2:n.2209C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_138149.2:n.2293C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Holt-Oram syndrome (HOS)
Synonyms:: Ventriculo-radial syndrome; Atrio digital syndrome; Cardiac-limb syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007732; MedGen: C0265264; Orphanet: 392; OMIM: 142900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001420990	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jul 24, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25046559, 27782106, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001420990

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jul 24, 2020)

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

Whole exome sequencing for the identification of a new mutation in TGFB2 involved in a familial case of non-syndromic aortic disease.

Gago-Díaz M, Blanco-Verea A, Teixidó-Turà G, Valenzuela I, Del Campo M, Borregan M, Sobrino B, Amigo J, García-Dorado D, Evangelista A, Carracedo A, Brion M.

Clin Chim Acta. 2014 Nov 1;437:88-92. doi: 10.1016/j.cca.2014.07.016. Epub 2014 Jul 19.

PubMed [citation]

PMID:: 25046559

A missense TGFB2 variant p.(Arg320Cys) causes a paradoxical and striking increase in aortic TGFB1/2 expression.

Al Maskari R, Yasmin, Cleary S, Figg N, Mehta S, Rassl D, Wilkinson I, O'Shaughnessy KM.

Eur J Hum Genet. 2016 Jan;25(1):157-160. doi: 10.1038/ejhg.2016.143. Epub 2016 Oct 26.

PubMed [citation]

PMID:: 27782106
PMCID:: PMC5149071

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001420990.2

#	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 arginine with cysteine at codon 320 of the TGFB2 protein (p.Arg320Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of TGFB2-related conditions (PMID: 25046559, 27782106, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495213). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been 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: Jan 26, 2022

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