NM_000071.3(CBS):c.572C>T (p.Thr191Met) AND Classic homocystinuria

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Mar 23, 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:: RCV000576767.18

Allele description [Variation Report for NM_000071.3(CBS):c.572C>T (p.Thr191Met)]

NM_000071.3(CBS):c.572C>T (p.Thr191Met)

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.572C>T (p.Thr191Met)

Other names:

p.T191M:ACG>ATG

HGVS:

NC_000021.9:g.43065481G>A
NG_008938.1:g.15450C>T
NM_000071.3:c.572C>TMANE SELECT
NM_001178008.3:c.572C>T
NM_001178009.3:c.572C>T
NM_001320298.2:c.572C>T
NM_001321072.1:c.257C>T
NP_000062.1:p.Thr191Met
NP_000062.1:p.Thr191Met
NP_001171479.1:p.Thr191Met
NP_001171480.1:p.Thr191Met
NP_001307227.1:p.Thr191Met
NP_001308001.1:p.Thr86Met
LRG_777t1:c.572C>T
LRG_777:g.15450C>T
LRG_777p1:p.Thr191Met
NC_000021.8:g.44485591G>A
NM_000071.2:c.572C>T
P35520:p.Thr191Met

Protein change:

T191M; THR191MET

Links:

UniProtKB: P35520#VAR_008068; OMIM: 613381.0016; dbSNP: rs121964973

NCBI 1000 Genomes Browser:

rs121964973

Molecular consequence:

NM_000071.3:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.572C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.257C>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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000677987	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Pathogenic (Oct 27, 2015)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22267502, 22069143, 16429402, 10338090, 20506325, 12815602, 16470595 Citation Link,
SCV001452092	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002016940	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 27, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002512726	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002790934	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 9, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841740	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004213858	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 23, 2024)	unknown	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	unknown	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
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Surrogate genetics and metabolic profiling for characterization of human disease alleles.

Mayfield JA, Davies MW, Dimster-Denk D, Pleskac N, McCarthy S, Boydston EA, Fink L, Lin XX, Narain AS, Meighan M, Rine J.

Genetics. 2012 Apr;190(4):1309-23. doi: 10.1534/genetics.111.137471. Epub 2012 Jan 20. Erratum in: Genetics. 2012 Oct;192(2):759-60.

PubMed [citation]

PMID:: 22267502
PMCID:: PMC3316645

Cystathionine beta-synthase mutants exhibit changes in protein unfolding: conformational analysis of misfolded variants in crude cell extracts.

Hnízda A, Jurga V, Raková K, Kožich V.

J Inherit Metab Dis. 2012 May;35(3):469-77. doi: 10.1007/s10545-011-9407-4. Epub 2011 Nov 9.

PubMed [citation]

PMID:: 22069143
PMCID:: PMC3319881

See all PubMed Citations (8)

Details of each submission

From Counsyl, SCV000677987.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	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 Natera, Inc., SCV001452092.1

#	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 Revvity Omics, Revvity, SCV002016940.3

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV002512726.1

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

Description

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderate, PM3 very strong, PP3 supporting

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

From Fulgent Genetics, Fulgent Genetics, SCV002790934.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV003841740.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.93). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000132). A different missense change at the same codon (p.Thr191Lys) has been reported to be associated with CBS related disorder (ClinVar ID: VCV000431934). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Baylor Genetics, SCV004213858.2

#	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

Last Updated: Nov 24, 2024

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