NM_000071.3(CBS):c.1150A>G (p.Lys384Glu) AND HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Oct 11, 2023
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:: RCV003495103.1

Allele description [Variation Report for NM_000071.3(CBS):c.1150A>G (p.Lys384Glu)]

NM_000071.3(CBS):c.1150A>G (p.Lys384Glu)

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.1150A>G (p.Lys384Glu)

HGVS:

NC_000021.9:g.43059299T>C
NG_008938.1:g.21632A>G
NM_000071.3:c.1150A>GMANE SELECT
NM_001178008.3:c.1150A>G
NM_001178009.3:c.1150A>G
NM_001320298.2:c.1150A>G
NM_001321072.1:c.835A>G
NP_000062.1:p.Lys384Glu
NP_001171479.1:p.Lys384Glu
NP_001171480.1:p.Lys384Glu
NP_001307227.1:p.Lys384Glu
NP_001308001.1:p.Lys279Glu
LRG_777:g.21632A>G
NC_000021.8:g.44479409T>C
P35520:p.Lys384Glu

Protein change:

K279E; LYS384GLU

Links:

UniProtKB: P35520#VAR_002191; OMIM: 613381.0007; dbSNP: rs121964967

NCBI 1000 Genomes Browser:

rs121964967

Molecular consequence:

NM_000071.3:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.1150A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.835A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004283189	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 11, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8990018, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004283189

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 11, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004283189.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 384 of the CBS protein (p.Lys384Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with homocystinuria (PMID: 8990018). ClinVar contains an entry for this variant (Variation ID: 123). 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. 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.

#	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: Feb 20, 2024

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