21-43063045-C-T

Variant names:

• chr21-43063045-C-T
• rs141502207
• NM_000071.3:c.862G>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.862G>A​(p.Ala288Thr) 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. A288P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 5.05

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 strand (size 2) in uniprot entity CBS_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 21-43063045-C-T is Pathogenic according to our data. Variant chr21-43063045-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43063045-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.862G>A	p.Ala288Thr	missense_variant	Exon 10 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.862G>A	p.Ala288Thr	missense_variant	Exon 10 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251262 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135830

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: 0.0000466

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:2 Uncertain:1

Mar 22, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 16205833). Functional assays showed that the variant had supporting level of impact on gene/protein function (PMID: 16205833). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.849>=0.6, 3CNET: 0.96>=0.75). A missense variant is a common mechanism. It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001192201, PMID:15365998). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Dec 28, 2017

Counsyl

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Nov 17, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jul 22, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.862G>A (p.A288T) alteration is located in exon 10 (coding exon 8) of the CBS gene. This alteration results from a G to A substitution at nucleotide position 862, causing the alanine (A) at amino acid position 288 to be replaced by a threonine (T). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251262) total alleles studied. The highest observed frequency was <0.01% (1/21470) of European (Finnish) alleles. This alteration has been detected in the compound heterozygous state in trans with another pathogenic CBS alteration in an individual with CBS-related homocystinuria (Lee, 2005). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, A288T is slightly disruptive to the structure (McCorvie, 2014). Thin-layer chromatography analysis of NIH3T3 cells expressing p.A288T showed an approximate 96% reduction in enzymatic activity compared to wild-type (Lee, 2005). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Homocystinuria Pathogenic:1

Aug 10, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.862G>A (p.Ala288Thr) 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 251262 control chromosomes. c.862G>A has been reported in the literature as a compound heterozygous genotype or without a second allele specified in at-least two individuals affected with Homocystinuria (example, Lee_2005, Bermudez_2006). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Lee_2005). The most pronounced variant effect results in 4-6% of normal enzyme activity in-vitro. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	.;.;.;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;M;M;M
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.89
MutPred		0.79		Gain of glycosylation at A288 (P = 0.0734);Gain of glycosylation at A288 (P = 0.0734);Gain of glycosylation at A288 (P = 0.0734);Gain of glycosylation at A288 (P = 0.0734);
MVP		0.91
MPC		1.0
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.82
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs141502207; hg19: chr21-44483155;