rs786204466

Positions:

• chr21-43053969-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.1566del​(p.Lys523SerfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G522G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -1.23

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PP5: Variant 21-43053969-TC-T is Pathogenic according to our data. Variant chr21-43053969-TC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188784.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43053969-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.1566del	p.Lys523SerfsTer18	frameshift_variant	17/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.1566del	p.Lys523SerfsTer18	frameshift_variant	17/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 14, 2014	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this premature translational stop signal affects CBS function (PMID: 25044645). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 188784). This premature translational stop signal has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 12815602, 21520339). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys523Serfs*18) in the CBS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the CBS protein. -

Homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Mar 19, 2020

Variant summary: CBS c.1566delG (p.Lys523SerfsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant was absent in 248894 control chromosomes (gnomAD). c.1566delG has been reported in the literature in individuals affected with Homocystinuria and patients who were in compound heterozygous or homozygous states displayed null CBS activity (Castro_2001, Urreizti_2003) . These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs786204466; hg19: chr21-44474079;