NM_000071.3(CBS):c.992C>A (p.Ala331Glu) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 27, 2023
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:: RCV002228833.14

Allele description [Variation Report for NM_000071.3(CBS):c.992C>A (p.Ala331Glu)]

NM_000071.3(CBS):c.992C>A (p.Ala331Glu)

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.992C>A (p.Ala331Glu)

Other names:

p.A331E:GCG>GAG

HGVS:

NC_000021.9:g.43062358G>T
NG_008938.1:g.18573C>A
NM_000071.3:c.992C>AMANE SELECT
NM_001178008.3:c.992C>A
NM_001178009.3:c.992C>A
NM_001320298.2:c.992C>A
NM_001321072.1:c.677C>A
NP_000062.1:p.Ala331Glu
NP_000062.1:p.Ala331Glu
NP_001171479.1:p.Ala331Glu
NP_001171480.1:p.Ala331Glu
NP_001307227.1:p.Ala331Glu
NP_001308001.1:p.Ala226Glu
LRG_777t1:c.992C>A
LRG_777:g.18573C>A
LRG_777p1:p.Ala331Glu
NC_000021.8:g.44482468G>T
NM_000071.2:c.992C>A
P35520:p.Ala331Glu

Protein change:

A226E

Links:

UniProtKB: P35520#VAR_008079; dbSNP: rs777919630

NCBI 1000 Genomes Browser:

rs777919630

Molecular consequence:

NM_000071.3:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.992C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.677C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000649853	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9156316, 22267502, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000649853

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 27, 2023)

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

Characterisation of five missense mutations in the cystathionine beta-synthase gene from three patients with B6-nonresponsive homocystinuria.

Dawson PA, Cox AJ, Emmerson BT, Dudman NP, Kraus JP, Gordon RB.

Eur J Hum Genet. 1997 Jan-Feb;5(1):15-21.

PubMed [citation]

PMID:: 9156316

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000649853.7

#	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 alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 331 of the CBS protein (p.Ala331Glu). This variant is present in population databases (rs777919630, gnomAD 0.0009%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9156316; Invitae). ClinVar contains an entry for this variant (Variation ID: 212857). 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%. Experimental studies have shown that this missense change affects CBS function (PMID: 9156316, 22267502). For these reasons, this variant has been 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: Nov 24, 2024

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