NM_000071.2(CBS):c.302T>C (p.Leu101Pro) AND Classic homocystinuria

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Aug 27, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000169617.5

Allele description [Variation Report for NM_000071.2(CBS):c.302T>C (p.Leu101Pro)]

NM_000071.2(CBS):c.302T>C (p.Leu101Pro)

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.302T>C (p.Leu101Pro)
HGVS:
  • NC_000021.9:g.43068523A>G
  • NG_008938.1:g.12408T>C
  • NM_000071.2:c.302T>C
  • NM_001178008.2:c.302T>C
  • NM_001178009.3:c.302T>C
  • NM_001320298.1:c.302T>C
  • NP_000062.1:p.Leu101Pro
  • NP_001171479.1:p.Leu101Pro
  • NP_001171480.1:p.Leu101Pro
  • NP_001307227.1:p.Leu101Pro
  • LRG_777t1:c.302T>C
  • LRG_777:g.12408T>C
  • LRG_777p1:p.Leu101Pro
  • NC_000021.8:g.44488633A>G
  • P35520:p.Leu101Pro
Protein change:
L101P
Links:
UniProtKB: P35520#VAR_021791; dbSNP: rs786204757
NCBI 1000 Genomes Browser:
rs786204757
Molecular consequence:
  • NM_000071.2:c.302T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178008.2:c.302T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178009.3:c.302T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320298.1:c.302T>C - 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
SCV000221143Counsylcriteria provided, single submitter
Likely pathogenic
(Feb 18, 2015)
unknownliterature only

PubMed (8)
[See all records that cite these PMIDs]

Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015),

Citation Link,

SCV000826966Invitaecriteria provided, single submitter
Pathogenic
(Aug 27, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Testing computational prediction of missense mutation phenotypes: functional characterization of 204 mutations of human cystathionine beta synthase.

Wei Q, Wang L, Wang Q, Kruger WD, Dunbrack RL Jr.

Proteins. 2010 Jul;78(9):2058-74. doi: 10.1002/prot.22722.

PubMed [citation]
PMID:
20455263
PMCID:
PMC3040297

Structural insights into mutations of cystathionine beta-synthase.

Meier M, Oliveriusova J, Kraus JP, Burkhard P.

Biochim Biophys Acta. 2003 Apr 11;1647(1-2):206-13. Review.

PubMed [citation]
PMID:
12686134
See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000221143.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (8)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000826966.4

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

Description

This sequence change replaces leucine with proline at codon 101 of the CBS protein (p.Leu101Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the homozygous or compound-heterozygous state in several individuals and families affected with cystathionine β-synthase (CBS) deficiency (PMID: 9889017, 12124992, 14635102). ClinVar contains an entry for this variant (Variation ID: 189185). Experimental studies in yeast and E. coli have shown that this missense change results in complete loss of enzymatic activity (PMID: 22267502, 20066033, 14635102, 12124992). 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 7, 2021

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