21-43065481-G-T

Variant names:

• chr21-43065481-G-T
• rs121964973
• NM_000071.3:c.572C>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM5 PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.572C>A​(p.Thr191Lys) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T191M) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 4)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.36

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065481-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 21-43065481-G-T is Pathogenic according to our data. Variant chr21-43065481-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431934.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.572C>A	p.Thr191Lys	missense_variant	Exon 7 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.572C>A	p.Thr191Lys	missense_variant	Exon 7 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 4

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 4

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Oct 30, 2015

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

While the likely pathogenic T191K variant in the CBS gene has not been reported to our knowledge, a pathogenic variant affecting this same residue, T191M, has been reported in association with homocystinuria due to cystathionine beta-synthase (CBS) deficiency (Kraus et al., 1999). Additionally, variants in nearby residues (D198V, P200L) have been reported in the Human Gene Mutation Database in association with homocystinuria (Stenson et al., 2014), further supporting the functional importance of this residue and this region of the protein. T191K results in a semi-conservative amino acid substitution at a position that is conserved across species, and is located in the exposed periphery of the active core of the CBS protein. Consequently, in silico analysis predicts T191K is probably damaging to the protein structure/function. Furthermore, T191K was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, this variant is likely pathogenic -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	.;.;.;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.84		Gain of catalytic residue at T191 (P = 0.0149);Gain of catalytic residue at T191 (P = 0.0149);Gain of catalytic residue at T191 (P = 0.0149);Gain of catalytic residue at T191 (P = 0.0149);
MVP		0.92
MPC		1.2
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.98
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: rs121964973; hg19: chr21-44485591;