21-43066332-C-T

Position:

chr21-43066332-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.362G>A(p.Arg121His) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging 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. R121C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 9)

Exomes 𝑓: 0.0000088 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.84

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 16 ACMG points.

PM1

In a helix (size 13) in uniprot entity CBS_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066333-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 21-43066332-C-T is Pathogenic according to our data. Variant chr21-43066332-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066332-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.362G>A	p.Arg121His	missense_variant	5/17	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.362G>A	p.Arg121His	missense_variant	5/17	1	NM_000071.3	ENSP00000381231.4		P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

74826

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251070

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.000185

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000885

AC:

AN:

791080

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

410534

show subpopulations

Gnomad4 AFR exome

AF:

0.0000699

Gnomad4 AMR exome

AF:

0.0000249

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000292

Gnomad4 NFE exome

AF:

0.00000556

Gnomad4 OTH exome

AF:

0.0000270

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

74826

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35968

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000495

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 15, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 03, 2021	NM_000071.2(CBS):c.362G>A(R121H) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. R121H has been observed in cases with relevant disease (PMID: 10338090, 16307898, 16479318, 30873612). Functional assessments of this variant are available in the literature (PMID: 16307898, 22267502). R121H has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000071.2(CBS):c.362G>A(R121H) 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. -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2022

The p.R121H pathogenic mutation (also known as c.362G>A), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 362. The arginine at codon 121 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states with other alterations in CBS in several individuals with homocystinuria, features of homocystinuria and/or CBS-deficiency (Kraus JP et al. Hum Mutat, 1999;13:362-75; Urreizti R et al. J Hum Genet, 2006 Feb;51:305-313; Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8; Van Hove JLK et al. J Inherit Metab Dis, 2019 05;42:424-437). In expression studies in E. coli, this variant showed decreased enzyme activity and impaired capability to correctly form tetramers (Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8). In a yeast growth assay, this variant was characterized as nonfunctional (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Nov 05, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 121 of the CBS protein (p.Arg121His). This variant is present in population databases (rs770095972, gnomAD 0.03%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 16479318). ClinVar contains an entry for this variant (Variation ID: 188948). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 16307898, 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 16307898, 21520339; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 31, 2020

Variant summary: CBS c.362G>A (p.Arg121His) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251070 control chromosomes. c.362G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example, Katsushima_2006, Urreizti_2006, Kraus_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severely impaired enzyme activity resulting from impaired tetramer assembly (Katsushima_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D;D;D;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.67

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

1.0

.;.;.;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.95

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.8

H;H;H;H;.

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.0

D;D;D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.96

MVP

0.95

MPC

1.3

ClinPred

1.0

GERP RS

4.4

Varity_R

0.96

gMVP

0.97

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