rs398123151

chr21-43062344-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.1006C>T(p.Arg336Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R336H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 8.70

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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062343-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 21-43062344-G-A is Pathogenic according to our data. Variant chr21-43062344-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062344-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.1006C>T	p.Arg336Cys	missense_variant	11/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.1006C>T	p.Arg336Cys	missense_variant	11/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 250690 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135676

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: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2302 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1212

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000642 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:7 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 21, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 12, 2023	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 25, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 17, 2024	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2021	Reported to be a founder mutation in the Qatari population, affecting approximately 1 in 1,8000 births (Gan-Schreier et al., 2010; El Bashir et al., 2015); Functional studies showed reduced activity of R336C in mammalian (Ismail et al., 2019) and E-coli expression systems (Urreizti et al., 2006); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 31240737, 26582918, 30408270, 12815602, 19914636, 27629047, 25218699, 25712383, 7762555, 23685761, 26464485, 10408774, 21517828, 16786517, 21240075, 7967489, 21062078, 16429402, 12124992, 16205833, 19370759, 20455263, 30968424, 31130284) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 26, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 06, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 336 of the CBS protein (p.Arg336Cys). This variant is present in population databases (rs398123151, gnomAD 0.004%). This missense change has been observed in individual(s) with homocystinuria (PMID: 12815602, 16205833, 21517828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92423). 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. Experimental studies have shown that this missense change affects CBS function (PMID: 10408774, 16205833, 16429402, 26464485). This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9870207, 23974653, 25218699). 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

Dec 09, 2020

Variant summary: CBS c.1006C>T (p.Arg336Cys) 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 2e-05 in 250690 control chromosomes (gnomAD). The variant, c.1006C>T, has been reported in the literature in several homozygous and compound heterozygous individuals affected with Homocystinuria (e.g. deFranchis_1999, Urreizti_2003, El-Said_2006, Zaidi_2012); in addition, the variant was identified as a founder mutation in Qatar (El-Said_2006). These data indicate that the variant is very likely to be associated with disease. Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzymatic activity (see e.g. deFranchis_1999, Urreizti_2003, Urreizti_2006, Mendes_2015), in addition, recently a transgenic mouse model was also developed with mice showing marked elevation in serum homocysteine (Gupta_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

CBS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

The CBS c.1006C>T variant is predicted to result in the amino acid substitution p.Arg336Cys. This variant has previously been reported in the homozygous state or with a second causative CBS variant in numerous patients with homocystinuria (Zaidi et al. 2011. PubMed ID: 21517828; Lee et al. 2005. PubMed ID: 16205833; Alcaide et al. 2014. PubMed ID: 25218699; Gaustadnes et al. 2002. PubMed ID: 12124992; de Franchis et al. 1999. PubMed ID: 10408774; Urreizti et al. 2003. PubMed ID: 12815602). This is the most commonly reported causative variant in the CBS gene in individuals in Qatar (El-Said et al. 2006. PubMed ID: 16786517; Zschocke et al. 2009. PubMed ID: 19370759). A different substitution affecting the same amino acid (p.Arg336His) was also reported in patients with homocystinuria (Coude et al.1998. PubMed ID: 9870207; Kumar et al. 2022. PubMed ID: 36065636). In vitro functional studies have shown that both p.Arg336Cys and p.Arg336His substitutions lead to decreased amount of protein and enzyme activity (Lee et al. 2005. PubMed ID: 16205833; Urreizti et al. 2006. PubMed ID: 16429402; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.8	D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.98
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.96

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: rs398123151; hg19: chr21-44482454;