NM_000071.3(CBS):c.1553-1G>C AND Classic homocystinuria

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Jul 26, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000669704.3

Allele description [Variation Report for NM_000071.3(CBS):c.1553-1G>C]

NM_000071.3(CBS):c.1553-1G>C

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.1553-1G>C
HGVS:
  • NC_000021.9:g.43053984C>G
  • NG_008938.1:g.26947G>C
  • NM_000071.2:c.1553-1G>C
  • NM_000071.3:c.1553-1G>CMANE SELECT
  • NM_001178008.3:c.1553-1G>C
  • NM_001178009.3:c.1553-1G>C
  • NM_001320298.2:c.1553-1G>C
  • NM_001321072.1:c.1238-1G>C
  • LRG_777t1:c.1553-1G>C
  • LRG_777:g.26947G>C
  • NC_000021.8:g.44474094C>G
Links:
dbSNP: rs1555869979
NCBI 1000 Genomes Browser:
rs1555869979
Molecular consequence:
  • NM_000071.2:c.1553-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_000071.3:c.1553-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001178008.3:c.1553-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001178009.3:c.1553-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001320298.2:c.1553-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_001321072.1:c.1238-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000794481Counsylcriteria provided, single submitter
Likely pathogenic
(Sep 27, 2017)
unknownclinical testing

Citation Link,

SCV000828223Invitaecriteria provided, single submitter
Uncertain significance
(Jul 26, 2018)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Counsyl, SCV000794481.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000828223.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This sequence change affects an acceptor splice site in the last intron (intron 16) of the CBS gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in combination with another pathogenic CBS variant in an individual affected with homocystinuria due to CBS deficiency (Invitae). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 25, 2021

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