NM_000071.3(CBS):c.19dup (p.Gln7fs) AND Homocystinuria

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Apr 26, 2019
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:: RCV001193390.1

Allele description [Variation Report for NM_000071.3(CBS):c.19dup (p.Gln7fs)]

NM_000071.3(CBS):c.19dup (p.Gln7fs)

Gene:

CBS:cystathionine beta-synthase [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_000071.3(CBS):c.19dup (p.Gln7fs)

HGVS:

NC_000021.8:g.44492284_44492285insG
NC_000021.9:g.43072180dup
NG_008938.1:g.8756dup
NM_000071.3:c.19dupMANE SELECT
NM_001178008.3:c.19dup
NM_001178009.3:c.19dup
NM_001320298.2:c.19dup
NP_000062.1:p.Gln7fs
NP_000062.1:p.Gln7fs
NP_001171479.1:p.Gln7fs
NP_001171480.1:p.Gln7fs
NP_001307227.1:p.Gln7fs
LRG_777t1:c.19dup
LRG_777:g.8756dup
LRG_777p1:p.Gln7fs
NC_000021.8:g.44492284_44492285insG
NC_000021.8:g.44492290dup
NC_000021.8:g.44492290dupG
NM_000071.2:c.19dup
NM_000071.2:c.19dupC
NM_000071.3:c.19dupCMANE SELECT

Protein change:

Q7fs

Links:

dbSNP: rs748695461

NCBI 1000 Genomes Browser:

rs748695461

Molecular consequence:

NM_000071.3:c.19dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001178008.3:c.19dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001178009.3:c.19dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001320298.2:c.19dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001362175	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 26, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 12124992, 25218699 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001362175

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 26, 2019)

germline

clinical testing

PubMed (2)
[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 Australian patients: genotype-phenotype correlations and response to treatment.

Gaustadnes M, Wilcken B, Oliveriusova J, McGill J, Fletcher J, Kraus JP, Wilcken DE.

Hum Mutat. 2002 Aug;20(2):117-26.

PubMed [citation]

PMID:: 12124992

Enzymatic diagnosis of homocystinuria by determination of cystathionine-ß-synthase activity in plasma using LC-MS/MS.

Alcaide P, Krijt J, Ruiz-Sala P, Ješina P, Ugarte M, Kožich V, Merinero B.

Clin Chim Acta. 2015 Jan 1;438:261-5. doi: 10.1016/j.cca.2014.09.009. Epub 2014 Sep 16.

PubMed [citation]

PMID:: 25218699

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001362175.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: CBS c.19dupC (p.Gln7ProfsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.1e-06 in 243178 control chromosomes (gnomAD). c.19dupC has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Homocystinuria (Alcaide_2015, Gaustadnes_2002). These data indicate that the variant is very likely to be associated with disease. A compound heterozygote affected individual was found to have <10% CBS activity (Alcaide_2015). Three ClinVar submisions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was 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 13, 2024

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