NM_000071.3(CBS):c.1330G>A (p.Asp444Asn) AND Homocystinuria

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 30, 2017
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:: RCV000781196.9

Allele description [Variation Report for NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)]

NM_000071.3(CBS):c.1330G>A (p.Asp444Asn)

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.1330G>A (p.Asp444Asn)

Other names:

p.D444N:GAC>AAC; NM_000071.2(CBS):c.1330G>A(p.Asp444Asn); NM_001178008.1(CBS):c.1330G>A(p.Asp444Asn); NM_001178009.1(CBS):c.1330G>A(p.Asp444Asn)

HGVS:

NC_000021.9:g.43058862C>T
NG_008938.1:g.22069G>A
NM_000071.3:c.1330G>AMANE SELECT
NM_001178008.3:c.1330G>A
NM_001178009.3:c.1330G>A
NM_001320298.2:c.1330G>A
NM_001321072.1:c.1015G>A
NP_000062.1:p.Asp444Asn
NP_000062.1:p.Asp444Asn
NP_001171479.1:p.Asp444Asn
NP_001171480.1:p.Asp444Asn
NP_001307227.1:p.Asp444Asn
NP_001308001.1:p.Asp339Asn
LRG_777t1:c.1330G>A
LRG_777:g.22069G>A
LRG_777p1:p.Asp444Asn
NC_000021.8:g.44478972C>T
NM_000071.2:c.1330G>A
P35520:p.Asp444Asn

Protein change:

D339N; ASP444ASN

Links:

UniProtKB: P35520#VAR_002192; OMIM: 613381.0010; dbSNP: rs28934891

NCBI 1000 Genomes Browser:

rs28934891

Molecular consequence:

NM_000071.3:c.1330G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.1330G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.1330G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.1330G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.1015G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Homocystinuria
Identifiers:: MONDO: MONDO:0004737; MedGen: C0019880; Human Phenotype Ontology: HP:0002156

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000919081	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 30, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10364517, 20506325, 23974653, 8755636 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000919081

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 30, 2017)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

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 cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment.

Kluijtmans LA, Boers GH, Kraus JP, van den Heuvel LP, Cruysberg JR, Trijbels FJ, Blom HJ.

Am J Hum Genet. 1999 Jul;65(1):59-67.

PubMed [citation]

PMID:: 10364517
PMCID:: PMC1378075

Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity.

Kozich V, Sokolová J, Klatovská V, Krijt J, Janosík M, Jelínek K, Kraus JP.

Hum Mutat. 2010 Jul;31(7):809-19. doi: 10.1002/humu.21273.

PubMed [citation]

PMID:: 20506325
PMCID:: PMC2966864

See all PubMed Citations (4)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919081.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

Variant summary: The CBS c.1330G>A (p.Asp444Asn) variant involves the alteration of a conserved nucleotide that lies within the CBS domain (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 65/192534 control chromosomes at a frequency of 0.0003376, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been reported in numerous patients with CBS-related homocystinuria, including homozygous patients. Functional studies suggest that CBS expression and activity levels are similar to those found in heterozygous individuals, but binding with the necessary cofactor S-adenosylmethionine and the subsequent induction of CBS protein activity is impaired (Mendes_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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: Sep 16, 2024

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