21-43062343-C-A

Position:

• chr21-43062343-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM5 PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.1007G>T​(p.Arg336Leu) 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. R336C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.85

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 10 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CBS_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062344-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 21-43062343-C-A is Pathogenic according to our data. Variant chr21-43062343-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2908236.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1007G>T	p.Arg336Leu	missense_variant	11/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1007G>T	p.Arg336Leu	missense_variant	11/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 21, 2023

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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, 16429402, 22267502, 23974653, 25218699). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with CBS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 336 of the CBS protein (p.Arg336Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	.;.;.;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.4	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.96
MutPred		0.82		Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);Loss of solvent accessibility (P = 0.1077);
MVP		0.93
MPC		1.3
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.95
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

Other links and lift over

dbSNP: rs760417941; hg19: chr21-44482453;