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NM_000071.3(CBS):c.1616T>C (p.Leu539Ser) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 22, 2024
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:
RCV003597960.2

Allele description [Variation Report for NM_000071.3(CBS):c.1616T>C (p.Leu539Ser)]

NM_000071.3(CBS):c.1616T>C (p.Leu539Ser)

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.1616T>C (p.Leu539Ser)
HGVS:
  • NC_000021.9:g.43053920A>G
  • NG_008938.1:g.27011T>C
  • NM_000071.3:c.1616T>CMANE SELECT
  • NM_001178008.3:c.1616T>C
  • NM_001178009.3:c.1616T>C
  • NM_001320298.2:c.1616T>C
  • NM_001321072.1:c.1301T>C
  • NP_000062.1:p.Leu539Ser
  • NP_000062.1:p.Leu539Ser
  • NP_001171479.1:p.Leu539Ser
  • NP_001171480.1:p.Leu539Ser
  • NP_001307227.1:p.Leu539Ser
  • NP_001308001.1:p.Leu434Ser
  • LRG_777t1:c.1616T>C
  • LRG_777:g.27011T>C
  • LRG_777p1:p.Leu539Ser
  • NC_000021.8:g.44474030A>G
  • NM_000071.2:c.1616T>C
  • P35520:p.Leu539Ser
Protein change:
L434S; LEU539SER
Links:
UniProtKB: P35520#VAR_002194; OMIM: 613381.0008; dbSNP: rs121964968
NCBI 1000 Genomes Browser:
rs121964968
Molecular consequence:
  • NM_000071.3:c.1616T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178008.3:c.1616T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001178009.3:c.1616T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001320298.2:c.1616T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001321072.1:c.1301T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED
Identifiers:
MedGen: C3150344

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004534434Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jan 22, 2024) 		germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Two novel mutations (K384E and L539S) in the C-terminal moiety of the cystathionine beta-synthase protein in two French pyridoxine-responsive homocystinuria patients.

Aral B, Coudé M, London J, Aupetit J, Chassé JF, Zabot MT, Chadefaux-Vekemans B, Kamoun P.

Hum Mutat. 1997;9(1):81-2. No abstract available.

PubMed [citation]
PMID:
8990018

Cystathionine beta-synthase mutations: effect of mutation topology on folding and activity.

Kozich V, Sokolová J, Klatovská V, Krijt J, Janosík M, Jelínek K, Kraus JP.

Hum Mutat. 2010 Jul;31(7):809-19. doi: 10.1002/humu.21273.

PubMed [citation]
PMID:
20506325
PMCID:
PMC2966864
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004534434.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 539 of the CBS protein (p.Leu539Ser). This variant is present in population databases (rs121964968, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of homocystinuria due to CBS deficiency (PMID: 8990018). ClinVar contains an entry for this variant (Variation ID: 124). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 20506325). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Sep 29, 2024