NM_000071.3(CBS):c.1479G>A (p.Thr493=) AND Classic homocystinuria

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 26, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000471233.19

Allele description [Variation Report for NM_000071.3(CBS):c.1479G>A (p.Thr493=)]

NM_000071.3(CBS):c.1479G>A (p.Thr493=)

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.1479G>A (p.Thr493=)

Other names:

p.T493T:ACG>ACA

HGVS:

NC_000021.9:g.43056876C>T
NG_008938.1:g.24055G>A
NM_000071.3:c.1479G>AMANE SELECT
NM_001178008.3:c.1479G>A
NM_001178009.3:c.1479G>A
NM_001320298.2:c.1479G>A
NM_001321072.1:c.1164G>A
NP_000062.1:p.Thr493=
NP_000062.1:p.Thr493=
NP_001171479.1:p.Thr493=
NP_001171480.1:p.Thr493=
NP_001307227.1:p.Thr493=
NP_001308001.1:p.Thr388=
LRG_777t1:c.1479G>A
LRG_777:g.24055G>A
LRG_777p1:p.Thr493=
NC_000021.8:g.44476986C>T
NM_000071.2:c.1479G>A

Links:

dbSNP: rs143225442

NCBI 1000 Genomes Browser:

rs143225442

Molecular consequence:

NM_000071.3:c.1479G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001178008.3:c.1479G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001178009.3:c.1479G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001320298.2:c.1479G>A - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001321072.1:c.1164G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:: Classic homocystinuria
Synonyms:: HOMOCYSTINURIA WITH OR WITHOUT RESPONSE TO PYRIDOXINE; Homocystinuria due to CBS deficiency; Homocystinuria due to cystathionine beta-synthase deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009352; MedGen: C0751202; Orphanet: 394; OMIM: 236200

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001303145	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 13, 2018)	germline	clinical testing	Citation Link,
SCV003919772	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001303145

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 13, 2018)

germline

clinical testing

Citation Link,

SCV003919772

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 26, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001303145.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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

From Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003919772.1

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

Description

This variant has not been reported in the literature. This variant may be present in the general population, but population data for this variant is unreliable due to the presence of a highly homologous pseudogene. This variant is present in ClinVar, with classifications ranging from likely benign to variant of uncertain significance (Variation ID: 212834). This is a silent variant and does not change the amino acid, reducing the probability that this variant is disease causing. Splice prediction tools suggest that this variant may affect splicing, although further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. However, we cannot rule out the possibility that this variant is present in the pseudogene rather than in the real protein-coding gene.

#	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 26, 2024

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