NM_000071.3(CBS):c.263C>G (p.Pro88Arg) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 24, 2024
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:: RCV003496394.1

Allele description [Variation Report for NM_000071.3(CBS):c.263C>G (p.Pro88Arg)]

NM_000071.3(CBS):c.263C>G (p.Pro88Arg)

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.263C>G (p.Pro88Arg)

HGVS:

NC_000021.9:g.43068562G>C
NG_008938.1:g.12369C>G
NM_000071.3:c.263C>GMANE SELECT
NM_001178008.3:c.263C>G
NM_001178009.3:c.263C>G
NM_001320298.2:c.263C>G
NP_000062.1:p.Pro88Arg
NP_000062.1:p.Pro88Arg
NP_001171479.1:p.Pro88Arg
NP_001171480.1:p.Pro88Arg
NP_001307227.1:p.Pro88Arg
LRG_777t1:c.263C>G
LRG_777:g.12369C>G
LRG_777p1:p.Pro88Arg
NC_000021.8:g.44488672G>C
NM_000071.2:c.263C>G

Protein change:

P88R

Molecular consequence:

NM_000071.3:c.263C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.263C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.263C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.263C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Identifiers:: MedGen: C3150344

Recent activity

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ubiquitin-related protein 3 [Arabidopsis thaliana]
ubiquitin-related protein 3 [Arabidopsis thaliana]
gi|15221154|ref|NP_172662.1|

Protein
Protein kinase superfamily protein [Arabidopsis thaliana]
Protein kinase superfamily protein [Arabidopsis thaliana]
gi|15229823|ref|NP_189981.1|

Protein
5327513[uid] AND (alive[prop]) (1)
Gene
MAEO_RS06050 [Methanococcus aeolicus Nankai-3]
MAEO_RS06050 [Methanococcus aeolicus Nankai-3]
Gene ID:5327513

Gene
Gm47441 AND (alive[prop]) (0)
Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004264123	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 7762555, 22267502, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004264123

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 24, 2024)

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

The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations.

Sebastio G, Sperandeo MP, Panico M, de Franchis R, Kraus JP, Andria G.

Am J Hum Genet. 1995 Jun;56(6):1324-33.

PubMed [citation]

PMID:: 7762555
PMCID:: PMC1801112

Surrogate genetics and metabolic profiling for characterization of human disease alleles.

Mayfield JA, Davies MW, Dimster-Denk D, Pleskac N, McCarthy S, Boydston EA, Fink L, Lin XX, Narain AS, Meighan M, Rine J.

Genetics. 2012 Apr;190(4):1309-23. doi: 10.1534/genetics.111.137471. Epub 2012 Jan 20. Erratum in: Genetics. 2012 Oct;192(2):759-60.

PubMed [citation]

PMID:: 22267502
PMCID:: PMC3316645

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004264123.1

#	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 proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 88 of the CBS protein (p.Pro88Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CBS-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. This variant disrupts the p.Pro88 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7762555, 22267502). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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: Feb 20, 2024

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