rs886057100

chr21-43066321-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):c.373C>T(p.Arg125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R125Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 11)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.962

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066320-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 197625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 21-43066321-G-A is Pathogenic according to our data. Variant chr21-43066321-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 340089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066321-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.373C>T	p.Arg125Trp	missense_variant	5/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.373C>T	p.Arg125Trp	missense_variant	5/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 11

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251030 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000121 AC: 1 AN: 829620 Hom.: 0 Cov.: 12 AF XY: 0.00000233 AC XY: 1 AN XY: 429930

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000244

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 11

Alfa AF: 0.0000508 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:4

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	May 31, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 29, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CBS c.373C>T (p.Arg125Trp) variant has been reported in three studies in which it is found in a total of five individuals with homocystinuria, including two sets of siblings, all in a compound heterozygous state (Kluijtmans et al. 1999; Urreizti et al. 2003; Chwatko et al. 2007). Control data are unavailable for this variant, and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Functional studies in individual fibroblasts showed that the variant resulted in less than 2.5% of the CBS activity seen in unaffected individuals (Chwatko et al. 2007). Based on the evidence, the p.Arg125Trp variant is classified as likely pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 12, 2021	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 28, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 125 of the CBS protein (p.Arg125Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CBS deficiency (PMID: 10364517, 12815602, 24211323). ClinVar contains an entry for this variant (Variation ID: 340089). 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: 16429402). This variant disrupts the p.Arg125 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7849717, 9587029, 10338090, 12124992, 20308073, 20506325, 22612060). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 27, 2023

The CBS c.373C>T; p.Arg125Trp variant (rs886057100) is reported in the literature in individuals with cystathionine beta-synthase deficiency who carried an additional CBS variant (Chwatko 2007, Karaca 2014, Kluijtmans 1999). This variant is also reported in ClinVar (Variation ID: 340089). Functional analyses show the variant protein has decreased expression compared to wild type (Urreizti 2006), and CBS activity in patient derived fibroblasts was less than 2.5% compared to unaffected individuals (Chwatko 2007). This variant is only found on two alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.937). Additionally, a different variant at this codon (p.Arg125Gln) is reported in affected individuals and classified as pathogenic (see ClinVar Variation ID: 197625). Based on available information, the p.Arg125Trp variant is considered to be pathogenic. References: Chwatko G et al. Mutations in methylenetetrahydrofolate reductase or cystathionine beta-synthase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice. FASEB J. 2007 Jun;21(8):1707-13. PMID: 17327360. Karaca M et al. High prevalence of cerebral venous sinus thrombosis (CVST) as presentation of cystathionine beta-synthase deficiency in childhood: molecular and clinical findings of Turkish probands. Gene. 2014 Jan 25;534(2):197-203. PMID: 24211323. Kluijtmans LA et al. The molecular basis of cystathionine beta-synthase deficiency in Dutch patients with homocystinuria: effect of CBS genotype on biochemical and clinical phenotype and on response to treatment. Am J Hum Genet. 1999 Jul;65(1):59-67. PMID: 10364517. Urreizti R et al. Functional assays testing pathogenicity of 14 cystathionine-beta synthase mutations. Hum Mutat. 2006 Feb;27(2):211. PMID: 16429402. -

Homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 30, 2020

Variant summary: CBS c.373C>T (p.Arg125Trp) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) 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 8e-06 in 251030 control chromosomes (gnomAD). c.373C>T has been reported in the literature in multiple compound heterozygous individuals affected with Homocystinuria (Kluijtmans_1999, Urreizti_2003, Karaca_2014). These data indicate that the variant is likely to be associated with disease. Several publications also reported experimental evidence evaluating an impact on protein function, and demonstrated absent or less than 4% residual activities in patient derived fibroblasts (Kluijtmans_1999, Urreizti_2003) and in a bacterial expression system (Urreizti_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;.
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.17
FATHMM_MKL	Benign	0.67	D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.4	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.8	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.93
MutPred		0.92		Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);
MVP		0.91
MPC		1.1
ClinPred		0.98	D
GERP RS		2.1
Varity_R		0.93
gMVP		0.92

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

Other links and lift over

dbSNP: rs886057100; hg19: chr21-44486431;