NM_000071.3(CBS):c.770C>T (p.Thr257Met) AND Classic homocystinuria

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 13, 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:: RCV000169294.15

Allele description [Variation Report for NM_000071.3(CBS):c.770C>T (p.Thr257Met)]

NM_000071.3(CBS):c.770C>T (p.Thr257Met)

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.770C>T (p.Thr257Met)

Other names:

p.T257M:ACG>ATG

HGVS:

NC_000021.9:g.43063958G>A
NG_008938.1:g.16973C>T
NM_000071.3:c.770C>TMANE SELECT
NM_001178008.3:c.770C>T
NM_001178009.3:c.770C>T
NM_001320298.2:c.770C>T
NM_001321072.1:c.455C>T
NP_000062.1:p.Thr257Met
NP_000062.1:p.Thr257Met
NP_001171479.1:p.Thr257Met
NP_001171480.1:p.Thr257Met
NP_001307227.1:p.Thr257Met
NP_001308001.1:p.Thr152Met
LRG_777t1:c.770C>T
LRG_777:g.16973C>T
LRG_777p1:p.Thr257Met
NC_000021.8:g.44484068G>A
NM_000071.2:c.770C>T
P35520:p.Thr257Met

Protein change:

T152M

Links:

UniProtKB: P35520#VAR_002183; dbSNP: rs758236584

NCBI 1000 Genomes Browser:

rs758236584

Molecular consequence:

NM_000071.3:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.770C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.455C>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

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
SCV000220612	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Aug 21, 2014)	unknown	literature only	PubMed (7) [See all records that cite these PMIDs] 21517828, 16205833, 22977242, 16479318, 12686134, 22267502, 7762555 Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015), Citation Link,
SCV000930258	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001462121	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004213856	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 3, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847670	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 20, 2019)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 29600437, 16205833, 22267502, 29508359, 22977242, 7762555, 16479318, 21517828, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	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, literature only

Citations

PubMed

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

CBS mutations and MTFHR SNPs causative of hyperhomocysteinemia in Pakistani children.

Ibrahim S, Maqbool S, Azam M, Iqbal MP, Qamar R.

Mol Biol Rep. 2018 Jun;45(3):353-360. doi: 10.1007/s11033-018-4169-9. Epub 2018 Mar 29.

PubMed [citation]

PMID:: 29600437

See all PubMed Citations (10)

Details of each submission

From Counsyl, SCV000220612.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (7)

#	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 Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000930258.2

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001462121.1

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

#	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

From Baylor Genetics, SCV004213856.2

#	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, SCV004847670.1

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

Description

The p.Thr257Met variant in CBS has been reported in at least 7 individuals with homocystinuria (4 homozygous and 3 compound heterozygous) and segregated with disease in 2 affected individuals from 2 families (Ibrahim 2018, Lee 2005, Li 2018, Sebastio 1995, Urreizti 2006, Zaidi 2012). It has also been identified in 12/279982 total chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 188927). Computational prediction tools and conservation analysis 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 (Mayfield 2012, Yadav 2012, Sebastio 1995, Lee 2005). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2_Supporting, PP1, PP3, PP4.

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine