NM_000071.3(CBS):c.457G>A (p.Gly153Arg) AND Classic homocystinuria

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Aug 10, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000689266.14

Allele description [Variation Report for NM_000071.3(CBS):c.457G>A (p.Gly153Arg)]

NM_000071.3(CBS):c.457G>A (p.Gly153Arg)

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.457G>A (p.Gly153Arg)

HGVS:

NC_000021.9:g.43065690C>T
NG_008938.1:g.15241G>A
NM_000071.3:c.457G>AMANE SELECT
NM_001178008.3:c.457G>A
NM_001178009.3:c.457G>A
NM_001320298.2:c.457G>A
NM_001321072.1:c.142G>A
NP_000062.1:p.Gly153Arg
NP_000062.1:p.Gly153Arg
NP_001171479.1:p.Gly153Arg
NP_001171480.1:p.Gly153Arg
NP_001307227.1:p.Gly153Arg
NP_001308001.1:p.Gly48Arg
LRG_777t1:c.457G>A
LRG_777:g.15241G>A
LRG_777p1:p.Gly153Arg
NC_000021.8:g.44485800C>T
NM_000071.2:c.457G>A

Protein change:

G153R

Links:

dbSNP: rs745704046

NCBI 1000 Genomes Browser:

rs745704046

Molecular consequence:

NM_000071.3:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.457G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.142G>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
SCV002060058	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Uncertain significance (Nov 19, 2021)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30246729, 32000841, 22267502, 20455263, 16167124, 21517828 Citation Link,
SCV003927809	Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	no assertion criteria provided	Likely pathogenic (Apr 1, 2023)	germline	clinical testing
SCV004213887	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848896	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

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

Severe Hyperhomocysteinemia with Two Novel Mutations of c.154T>C and c.457G>A in Cystathionine Beta-Synthase Gene.

An H, Fan CQ, Duan JG, Ren Y, Dong K, Zhang Q, Ji XM, Huang XQ.

Chin Med J (Engl). 2018 Oct 5;131(19):2368-2370. doi: 10.4103/0366-6999.241801. No abstract available.

PubMed [citation]

PMID:: 30246729
PMCID:: PMC6166457

A proactive genotype-to-patient-phenotype map for cystathionine beta-synthase.

Sun S, Weile J, Verby M, Wu Y, Wang Y, Cote AG, Fotiadou I, Kitaygorodsky J, Vidal M, Rine J, Ješina P, Kožich V, Roth FP.

Genome Med. 2020 Jan 30;12(1):13. doi: 10.1186/s13073-020-0711-1.

PubMed [citation]

PMID:: 32000841
PMCID:: PMC6993387

See all PubMed Citations (7)

Details of each submission

From Myriad Genetics, Inc., SCV002060058.2

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

Description

NM_000071.2(CBS):c.457G>A(G153R) is a missense variant classified as a variant of uncertain significance in the context of homocystinuria, CBS-related. G153R has been observed in cases with relevant disease (PMID: 21517828, 16167124, 30246729). Functional assessments of this variant are available in the literature (PMID: 20455263, 22267502, 32000841). G153R has been observed in population frequency databases (gnomAD: NFE <0.002%). In summary, there is insufficient evidence to classify NM_000071.2(CBS):c.457G>A(G153R) as pathogenic or benign. 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 Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), SCV003927809.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213887.1

#	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

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848896.1

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

Description

The p.Gly153Arg variant in CBS has been reported in 1 individual severe hyperhomocysteinemia which was compound heterozygous with a pathogenic variant, and in 1 homozygous individual with homocystinuria which segregatred in an affected sibling (An 2013 PMID: 30246729, aidi 2012 PMID: 21517828). Biochemical examination in these individuals showed high plasma homocysteine levels (An 2013 PMID: 30246729, aidi 2012 PMID: 21517828), and in vitro functional studies support an impact to the protein (Mayfield 2012 PMID 22267502). The variant was absent in large population databases. It was reported in ClinVar (Variation ID 212846). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homcystinuria. ACMG/AMP criteria applied: PM3, PS3, PM2_Supporting, PP1, PP3, PP4.

#	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: Oct 8, 2024

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