NM_000071.3(CBS):c.362G>A (p.Arg121His) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 22, 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:: RCV002453568.2

Allele description [Variation Report for NM_000071.3(CBS):c.362G>A (p.Arg121His)]

NM_000071.3(CBS):c.362G>A (p.Arg121His)

Gene:

CBS:cystathionine beta-synthase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000071.3(CBS):c.362G>A (p.Arg121His)

HGVS:

NC_000021.9:g.43066332C>T
NG_008938.1:g.14599G>A
NM_000071.3:c.362G>AMANE SELECT
NM_001178008.3:c.362G>A
NM_001178009.3:c.362G>A
NM_001320298.2:c.362G>A
NM_001321072.1:c.47G>A
NP_000062.1:p.Arg121His
NP_000062.1:p.Arg121His
NP_001171479.1:p.Arg121His
NP_001171480.1:p.Arg121His
NP_001307227.1:p.Arg121His
NP_001308001.1:p.Arg16His
LRG_777t1:c.362G>A
LRG_777:g.14599G>A
LRG_777p1:p.Arg121His
NC_000021.8:g.44486442C>T
NM_000071.2:c.362G>A
P35520:p.Arg121His

Protein change:

R121H

Links:

UniProtKB: P35520#VAR_008055; dbSNP: rs770095972

NCBI 1000 Genomes Browser:

rs770095972

Molecular consequence:

NM_000071.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.362G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.47G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002615953	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jun 22, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 10338090, 16307898, 16479318, 22267502, 30873612, 31301157 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002615953

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jun 22, 2022)

germline

clinical testing

PubMed (6)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Cystathionine beta-synthase mutations in homocystinuria.

Kraus JP, Janosík M, Kozich V, Mandell R, Shih V, Sperandeo MP, Sebastio G, de Franchis R, Andria G, Kluijtmans LA, Blom H, Boers GH, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura T, Gaustadnes M.

Hum Mutat. 1999;13(5):362-75. Review.

PubMed [citation]

PMID:: 10338090

Expression study of mutant cystathionine beta-synthase found in Japanese patients with homocystinuria.

Katsushima F, Oliveriusova J, Sakamoto O, Ohura T, Kondo Y, Iinuma K, Kraus E, Stouracova R, Kraus JP.

Mol Genet Metab. 2006 Apr;87(4):323-8. Epub 2005 Nov 22.

PubMed [citation]

PMID:: 16307898

See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002615953.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The p.R121H pathogenic mutation (also known as c.362G>A), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 362. The arginine at codon 121 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states with other alterations in CBS in several individuals with homocystinuria, features of homocystinuria and/or CBS-deficiency (Kraus JP et al. Hum Mutat, 1999;13:362-75; Urreizti R et al. J Hum Genet, 2006 Feb;51:305-313; Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8; Van Hove JLK et al. J Inherit Metab Dis, 2019 05;42:424-437). In expression studies in E. coli, this variant showed decreased enzyme activity and impaired capability to correctly form tetramers (Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8). In a yeast growth assay, this variant was characterized as nonfunctional (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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: Sep 29, 2024

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