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

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Feb 15, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000169322.10

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:: Classic homocystinuria
Synonyms:: HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE; Homocystinuria due to CBS deficiency; Homocystinuria due to cystathionine beta-synthase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009352; MedGen: C0751202; Orphanet: 394; OMIM: 236200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001452099	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002060177	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 3, 2021)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16307898, 30873612, 22267502, 16479318, 10338090 Citation Link,
SCV004213844	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 15, 2024)	unknown	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

SCV001452099

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV002060177

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))

Likely pathogenic
(Nov 3, 2021)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV004213844

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 15, 2024)

unknown

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

Citations

PubMed

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

Biomarkers of oxidative stress, inflammation, and vascular dysfunction in inherited cystathionine β-synthase deficient homocystinuria and the impact of taurine treatment in a phase 1/2 human clinical trial.

Van Hove JLK, Freehauf CL, Ficicioglu C, Pena LDM, Moreau KL, Henthorn TK, Christians U, Jiang H, Cowan TM, Young SP, Hite M, Friederich MW, Stabler SP, Spector EB, Kronquist KE, Thomas JA, Emmett P, Harrington MJ, Pyle L, Creadon-Swindell G, Wempe MF, MacLean KN.

J Inherit Metab Dis. 2019 May;42(3):424-437. doi: 10.1002/jimd.12085. Epub 2019 Apr 11.

PubMed [citation]

PMID:: 30873612

See all PubMed Citations (6)

Details of each submission

From Natera, Inc., SCV001452099.1

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

From Myriad Genetics, Inc., SCV002060177.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

NM_000071.2(CBS):c.362G>A(R121H) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. R121H has been observed in cases with relevant disease (PMID: 10338090, 16307898, 16479318, 30873612). Functional assessments of this variant are available in the literature (PMID: 16307898, 22267502). R121H has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000071.2(CBS):c.362G>A(R121H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Baylor Genetics, SCV004213844.2

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

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

Last Updated: Sep 29, 2024

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