NM_000071.2(CBS):c.434C>T (p.Pro145Leu) AND Classic homocystinuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jun 29, 2019)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000625555.5

Allele description [Variation Report for NM_000071.2(CBS):c.434C>T (p.Pro145Leu)]

NM_000071.2(CBS):c.434C>T (p.Pro145Leu)

Gene:
CBS:cystathionine beta-synthase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
21q22.3
Genomic location:
Preferred name:
NM_000071.2(CBS):c.434C>T (p.Pro145Leu)
HGVS:
  • NC_000021.9:g.43066260G>A
  • NG_008938.1:g.14671C>T
  • NM_000071.2:c.434C>T
  • NM_001178008.2:c.434C>T
  • NM_001178009.3:c.434C>T
  • NM_001320298.1:c.434C>T
  • NM_001321072.1:c.119C>T
  • NP_000062.1:p.Pro145Leu
  • NP_001171479.1:p.Pro145Leu
  • NP_001171480.1:p.Pro145Leu
  • NP_001307227.1:p.Pro145Leu
  • NP_001308001.1:p.Pro40Leu
  • LRG_777t1:c.434C>T
  • LRG_777:g.14671C>T
  • LRG_777p1:p.Pro145Leu
  • NC_000021.8:g.44486370G>A
  • P35520:p.Pro145Leu
Protein change:
P145L; PRO145LEU
Links:
UniProtKB: P35520#VAR_002178; OMIM: 613381.0002; dbSNP: rs121964963
NCBI 1000 Genomes Browser:
rs121964963
Molecular consequence:
  • NM_000071.2:c.434C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178008.2:c.434C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178009.3:c.434C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320298.1:c.434C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321072.1:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000746051Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcareno assertion criteria providedPathogenic
(Sep 18, 2017)
germlineclinical testing

SCV000930439Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Likely pathogenic
(Apr 27, 2019)
inheritedclinical testing

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

SCV001393783Invitaecriteria provided, single submitter
Pathogenic
(Jun 29, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedinheritedyesnot providednot providednot providednot providednot providedclinical 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

High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands.

Karaca M, Hismi B, Ozgul RK, Karaca S, Yilmaz DY, Coskun T, Sivri HS, Tokatli A, Dursun A.

Gene. 2014 Jan 25;534(2):197-203. doi: 10.1016/j.gene.2013.10.060. Epub 2013 Nov 6.

PubMed [citation]
PMID:
24211323
See all PubMed Citations (7)

Details of each submission

From Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare, SCV000746051.1

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

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV000930439.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1inheritedyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001393783.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces proline with leucine at codon 145 of the CBS protein (p.Pro145Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with homocystinuria (PMID: 24211323, 8353501, 16479318, 25218699). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 118). This variant has been reported to affect CBS protein function (PMID: 8353501, 22267502). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2021

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