NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 24, 2022
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:: RCV003224094.1

Allele description [Variation Report for NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)]

NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)

Gene:

TGFBR1:transforming growth factor beta receptor 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q22.33

Genomic location:

Preferred name:

NM_004612.4(TGFBR1):c.722C>T (p.Ser241Leu)

HGVS:

NC_000009.12:g.99138006C>T
NG_007461.1:g.37877C>T
NM_001130916.3:c.491C>T
NM_001306210.2:c.734C>T
NM_004612.4:c.722C>TMANE SELECT
NP_001124388.1:p.Ser164Leu
NP_001293139.1:p.Ser245Leu
NP_004603.1:p.Ser241Leu
NC_000009.11:g.101900288C>T
NM_004612.2:c.722C>T
P36897:p.Ser241Leu

Protein change:

S164L; SER241LEU

Links:

UniProtKB: P36897#VAR_029482; OMIM: 190181.0005; dbSNP: rs111854391

NCBI 1000 Genomes Browser:

rs111854391

Molecular consequence:

NM_001130916.3:c.491C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306210.2:c.734C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004612.4:c.722C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

variation affecting protein function [Variation Ontology: 0003]

Condition(s)

Name:: Loeys-Dietz syndrome 1 (LDS1)
Synonyms:: Loeys-Dietz syndrome type 1A; Furlong syndrome; Aortic aneurysm syndrome, Loeys-Dietz type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012212; MedGen: C4551955; Orphanet: 60030; OMIM: 609192

Name:: Multiple self-healing squamous epithelioma (MSSE)
Synonyms:: MULTIPLE SELF-HEALING SQUAMOUS EPITHELIOMA, SUSCEPTIBILITY TO; Ferguson-Smith type epithelioma; ESS1 (formerly)
Identifiers:: MONDO: MONDO:0007566; MedGen: C0546476; Orphanet: 65748; OMIM: 132800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003920553	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 24, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003920553

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 24, 2022)

germline

clinical testing

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920553.1

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

Description

This variant has been reported in the literature in at least 10 individuals with clinical features suggestive of, or consistent with, Loeys-Dietz syndrome (Selected publications: Wooderchak-Donahue 2015 PIMD: 25944730; Jani 2020 PMID: 32152251; Yang 2020 PMID: 31915033; Nayak 2021 PMID: 33436942), and was found to segregate with disease in a mildly affected parent (Woolnough 2017 PMID: 28209770). In at least two individuals, the variant was determined to be de novo (Adès 2006 PMID: 16596670). This variant is not present in large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 12524). Functional studies in vitro and in patient-derived fibroblasts demonstrate that this variant impacts protein function (Barnett 2011 PMID: 21267002; Cardoso 2012 PMID: 22414221). Evolutionary conservation and computational prediction tools support a deleterious effect of this variant. In summary, this variant is 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: Mar 5, 2024

ClinVar

Relating variation to medicine