NM_000071.3(CBS):c.341C>T (p.Ala114Val) AND Classic homocystinuria

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 30, 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:: RCV000490533.20

Allele description [Variation Report for NM_000071.3(CBS):c.341C>T (p.Ala114Val)]

NM_000071.3(CBS):c.341C>T (p.Ala114Val)

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.341C>T (p.Ala114Val)

Other names:

p.A114V:GCG>GTG

HGVS:

NC_000021.9:g.43066353G>A
NG_008938.1:g.14578C>T
NM_000071.3:c.341C>TMANE SELECT
NM_001178008.3:c.341C>T
NM_001178009.3:c.341C>T
NM_001320298.2:c.341C>T
NM_001321072.1:c.26C>T
NP_000062.1:p.Ala114Val
NP_000062.1:p.Ala114Val
NP_001171479.1:p.Ala114Val
NP_001171480.1:p.Ala114Val
NP_001307227.1:p.Ala114Val
NP_001308001.1:p.Ala9Val
LRG_777t1:c.341C>T
LRG_777:g.14578C>T
LRG_777p1:p.Ala114Val
NC_000021.8:g.44486463G>A
NM_000071.2:c.341C>T
P35520:p.Ala114Val

Protein change:

A114V; ALA114VAL

Links:

UniProtKB: P35520#VAR_002174; OMIM: 613381.0003; dbSNP: rs121964964

NCBI 1000 Genomes Browser:

rs121964964

Molecular consequence:

NM_000071.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178008.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001178009.3:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001320298.2:c.341C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001321072.1:c.26C>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
SCV000267240	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 18, 2016)	germline	reference population	PubMed (4) [See all records that cite these PMIDs] 8353501, 20490928, 20506325, 25741868
SCV000678069	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Mar 1, 2017)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 22267502, 10408774, 12686134, 8353501, 9587029, 20506325, 16307898, 22612060 Citation Link,
SCV000746328	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000893556	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001369940	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 16, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001443030	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2020)	biparental	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001524388	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002769356	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22069143, 32232970, 25741868
SCV005052057	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	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	inherited	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	curation
not provided	biparental	yes	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	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
East Asian	germline	unknown	1	not provided	not provided	not provided	not provided	reference population

Citations

PubMed

Restoring assembly and activity of cystathionine β-synthase mutants by ligands and chemical chaperones.

Kopecká J, Krijt J, Raková K, Kožich V.

J Inherit Metab Dis. 2011 Feb;34(1):39-48. doi: 10.1007/s10545-010-9087-5. Epub 2010 May 20.

PubMed [citation]

PMID:: 20490928
PMCID:: PMC3026675

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

See all PubMed Citations (12)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center, SCV000267240.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	East Asian	1	not provided	not provided	reference population	PubMed (4)

#	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		1	not provided	not provided	not provided

From Counsyl, SCV000678069.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

#	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, SCV000746328.1

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

From Fulgent Genetics, Fulgent Genetics, SCV000893556.1

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001369940.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PS3,PM2,PM5.

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV001443030.1

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

Description

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PS3,PS4_moderate,PM2,PM3,PP3

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

From Baylor Genetics, SCV001524388.2

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002769356.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with B6-responsive and non-responsive types homocystinuria, and hyperhomocysteinemic thrombosis (MIM#236200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated PALP domain (PDB). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. An alternative change at the same residue (p.Ala114Thr) has been reported as likely pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic multiple times, in patients with homocystinuria (ClinVar, LOVD, PMID: 32232970). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been proven to have mild effects on function, reducing enzyme activity, tetramer formation and protein instability (PMID: 22069143). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005052057.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

Relating variation to medicine