21-43058215-G-T

Variant names:

• chr21-43058215-G-T
• rs121964971
• NM_000071.3:c.1397C>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000071.3(CBS):​c.1397C>A​(p.Ser466*) variant causes a stop gained change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S466S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.42
• Publications: 0 publications found

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]

CBS Gene-Disease associations (from GenCC):

• classic homocystinuria

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 21-43058215-G-T is Pathogenic according to our data. Variant chr21-43058215-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1073191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 17	NP_000062.1
	CBS	NM_001178008.3		c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.1397C>A	p.Ser466*	stop_gained	Exon 15 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:2

Feb 24, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 08, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser466*) in the CBS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CBS are known to be pathogenic (PMID: 10338090, 12124992). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CBS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1073191). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		6.4
Vest4		0.94
ClinPred		0.99	D
GERP RS		4.6
Mutation Taster		=4/196	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121964971; hg19: chr21-44478325;