rs121964969

Positions:

chr21-43063931-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000071.3(CBS):c.797G>A(p.Arg266Lys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R266G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 4)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.85

Variant links:

Genes affected

CBS (HGNC:1550): (cystathionine beta-synthase) The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by adenosyl-methionine and uses pyridoxal phosphate as a cofactor. Defects in this gene can cause cystathionine beta-synthase deficiency (CBSD), which can lead to homocystinuria. This gene is a major contributor to cellular hydrogen sulfide production. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2016]

CBS links:

CBS (HGNC:):

CBS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a helix (size 12) in uniprot entity CBS_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.912

PP5

Variant 21-43063931-C-T is Pathogenic according to our data. Variant chr21-43063931-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 125.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43063931-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.797G>A	p.Arg266Lys	missense_variant	9/17	ENST00000398165.8	NP_000062.1	P35520-1Q9NTF0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.797G>A	p.Arg266Lys	missense_variant	9/17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000801

AC:

AN:

249680

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000146

AC:

AN:

205802

Hom.:

Cov.:

AF XY:

0.0000183

AC XY:

AN XY:

109370

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000281

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000413

Hom.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2024	- -

Homocystinuria, pyridoxine-responsive

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1997

- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2017

The p.R266K pathogenic mutation (also known as c.797G>A), located in coding exon 7 of the CBS gene, results from a G to A substitution at nucleotide position 797. The arginine at codon 266 is replaced by lysine, an amino acid with highly similar properties. This mutation has been reported in the homozygous state in several Norwegian patients with homocystinuria (Kim CE et al. Hum. Mol. Genet. 1997;6:2213-21). It has also been identified in the heterozygous state in two individuals with homocystinuria in whom the second allele is unknown (Kim CE et al. Hum. Mol. Genet. 1997;6:2213-21; Moat SJ et al. Hum. Mutat. 2004;23:206). Multiple labs have shown that this alteration leads to reduced enzyme activity and decreased stability of the CBS protein in vitro (e.g., Chen X et al. Hum. Mutat. 2006;27:474-82; Singh S et al. J. Inorg. Biochem. 2009;103:689-97; Kozich V et al. Hum. Mutat. 2010;31:809-19; Kopecká J et al. J. Inherit. Metab. Dis. 2011;34:39-48; Melenovská P et al. J. Inherit. Metab. Dis. 2015;38:287-94). In addition, a transgenic mouse model expressing this alteration exhibits reduced CBS enzyme activity, increased proteasomal degradation of the CBS protein, and elevated levels of total homocysteine in serum (Gupta S et al. Hum. Mutat. 2017;38:863-869). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 29, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CBS function (PMID: 9361025, 16619244, 20506325, 22267502, 22333527, 22612060, 22738154). 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. ClinVar contains an entry for this variant (Variation ID: 125). This missense change has been observed in individuals with pyridoxine-responsive CBS deficiency (PMID: 9361025). This variant is present in population databases (rs121964969, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 266 of the CBS protein (p.Arg266Lys). -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 13, 2020

Published functional studies demonstrate a damaging effect (Kim et al., 1997; Kozich et al., 2010; Majtan et al., 2012); Reported as pathogenic/likely pathogenic in ClinVar but additional evidence is not available (SCV000543517.2, SCV000738475.2, SCV000790684.1; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31301157, 9361025, 19232736, 11343305, 12686134, 15192637, 16619244, 20490928, 25331909, 28488385, 22333527, 20506325, 22267502, 22738154, 22612060, 14722927) -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 15, 2022

Variant summary: CBS c.797G>A (p.Arg266Lys) results in a conservative amino acid change located in the pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249680 control chromosomes (gnomAD) and c.797G>A has been reported in the literature in multiple individuals affected with Homocystinuria (e.g. Guttormsen_2001, Moat_2004). These data indicate that the variant is very likely to be associated with disease. The variant is responsive to pyridoxine therapy (Guttormsen_2001). The effect of this variant on its enzymatic function has been characterized in detail. Several in vitro experiments suggest that this variant moderately reduces enzymatic activity (e.g. Chen _2006, Kozich _2010). Furthermore, in transgenic mice expressing the p.R266K variant, Gupta et al demonstrated that the variant results in increased proteasomal degradation of the enzyme and found that CBS activity is reduced to only 2% of that in livers expressing wild-type human CBS (Gupta_2017). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as either pathogenic (n=3) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

.;.;.;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.91

D;D;D;D

MetaSVM

Pathogenic

0.89

MutationAssessor

Benign

0.99

L;L;L;L

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.6

D;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.77

P;P;P;P

Vest4

0.92

MVP

0.90

MPC

0.95

ClinPred

0.96

GERP RS

5.0

Varity_R

0.85

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over