NM_000071.3(CBS):c.430G>A (p.Glu144Lys) AND Classic homocystinuria

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Mar 15, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000169074.16

Allele description [Variation Report for NM_000071.3(CBS):c.430G>A (p.Glu144Lys)]

NM_000071.3(CBS):c.430G>A (p.Glu144Lys)

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.430G>A (p.Glu144Lys)

HGVS:

NC_000021.9:g.43066264C>T
NG_008938.1:g.14667G>A
NM_000071.3:c.430G>AMANE SELECT
NM_001178008.3:c.430G>A
NM_001178009.3:c.430G>A
NM_001320298.2:c.430G>A
NM_001321072.1:c.115G>A
NP_000062.1:p.Glu144Lys
NP_000062.1:p.Glu144Lys
NP_001171479.1:p.Glu144Lys
NP_001171480.1:p.Glu144Lys
NP_001307227.1:p.Glu144Lys
NP_001308001.1:p.Glu39Lys
LRG_777t1:c.430G>A
LRG_777:g.14667G>A
LRG_777p1:p.Glu144Lys
NC_000021.8:g.44486374C>T
NM_000071.2:c.430G>A
P35520:p.Glu144Lys

Protein change:

E144K; GLU144LYS

Links:

UniProtKB: P35520#VAR_002177; OMIM: 613381.0006; dbSNP: rs121964966

NCBI 1000 Genomes Browser:

rs121964966

Molecular consequence:

NM_000071.3:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.430G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.115G>A - 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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002060159	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Likely pathogenic (Nov 9, 2021)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 14722927, 25331909, 7611293, 12124992, 33057012, 20506325, 20490928, 22267502, 11359213 Citation Link,
SCV002543828	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004213898	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848730	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of cystathionine beta-synthase (CBS) deficiency in UK and US patients with homocystinuria.

Moat SJ, Bao L, Fowler B, Bonham JR, Walter JH, Kraus JP.

Hum Mutat. 2004 Feb;23(2):206. doi: 10.1002/humu.9214.

PubMed [citation]

PMID:: 14722927

Chaperone therapy for homocystinuria: the rescue of CBS mutations by heme arginate.

Melenovská P, Kopecká J, Krijt J, Hnízda A, Raková K, Janošík M, Wilcken B, Kožich V.

J Inherit Metab Dis. 2015 Mar;38(2):287-94. doi: 10.1007/s10545-014-9781-9. Epub 2014 Oct 21.

PubMed [citation]

PMID:: 25331909

See all PubMed Citations (10)

Details of each submission

From Myriad Genetics, Inc., SCV002060159.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

NM_000071.2(CBS):c.430G>A(E144K) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. E144K has been observed in cases with relevant disease (PMID: 14722927, 12124992, 11359213, 7611293, 33057012). Functional assessments of this variant are available in the literature (PMID: 25331909, 22267502, 20506325, 20490928). E144K has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, NM_000071.2(CBS):c.430G>A(E144K) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Suma Genomics, SCV002543828.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213898.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848730.1

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

Description

The p.Glu144Lys variant in CBS has been reported in at least 10 individuals with homocystinuria (Shih 1995 PMID: 7611293, Gordon 1998 PMID: 10215408, Gaustadnes 2002 PMID: 12124992, Kaur 2020 PMID: 33057012). It has also been identified in 0.0036% (2/55574) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 122). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies support an impact on protein function as the expression of enzymatic activity was found to be <1% of wild type in E. Coli and yeast (Gordon 1998 PMID: 10215408, Mayfield 2012 PMID: 22267502). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_VeryStrong, PM2_Supporting, PP3, PS3_Supporting. (This variant did not meet the variant calling quality criteria, and was included because it has been previously reported as a clinically significant variant.)

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine