NM_000071.3(CBS):c.341C>T (p.Ala114Val) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 30, 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:: RCV002227956.6

Allele description [Variation Report for NM_000071.3(CBS):c.341C>T (p.Ala114Val)]

NM_000071.3(CBS):c.341C>T (p.Ala114Val)

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.341C>T (p.Ala114Val)

Other names:

p.A114V:GCG>GTG

HGVS:

NC_000021.9:g.43066353G>A
NG_008938.1:g.14578C>T
NM_000071.3:c.341C>TMANE SELECT
NM_001178008.3:c.341C>T
NM_001178009.3:c.341C>T
NM_001320298.2:c.341C>T
NM_001321072.1:c.26C>T
NP_000062.1:p.Ala114Val
NP_000062.1:p.Ala114Val
NP_001171479.1:p.Ala114Val
NP_001171480.1:p.Ala114Val
NP_001307227.1:p.Ala114Val
NP_001308001.1:p.Ala9Val
LRG_777t1:c.341C>T
LRG_777:g.14578C>T
LRG_777p1:p.Ala114Val
NC_000021.8:g.44486463G>A
NM_000071.2:c.341C>T
P35520:p.Ala114Val

Protein change:

A114V; ALA114VAL

Links:

UniProtKB: P35520#VAR_002174; OMIM: 613381.0003; dbSNP: rs121964964

NCBI 1000 Genomes Browser:

rs121964964

Molecular consequence:

NM_000071.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.26C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Nme6 NME/NM23 nucleoside diphosphate kinase 6 [Rattus norvegicus]
Nme6 NME/NM23 nucleoside diphosphate kinase 6 [Rattus norvegicus]
Gene ID:58964

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000956328	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7762555, 8353501, 20490928, 20506325, 22069143, 22267502, 22612060, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000956328

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 30, 2024)

germline

clinical testing

PubMed (8)
[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

Molecular defect in a patient with pyridoxine-responsive homocystinuria.

Kozich V, de Franchis R, Kraus JP.

Hum Mol Genet. 1993 Jun;2(6):815-6. No abstract available.

PubMed [citation]

PMID:: 8353501

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000956328.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 114 of the CBS protein (p.Ala114Val). This variant is present in population databases (rs121964964, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria due to cystathionine-beta synthase (CBS) deficiency (PMID: 7762555, 8353501). ClinVar contains an entry for this variant (Variation ID: 119). 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: 20490928, 20506325, 22069143, 22267502, 22612060). 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: Oct 8, 2024

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