rs786204499
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000071.3(CBS):βc.689delβ(p.Leu230ArgfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. L230L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: π 0.000016 ( 1 hom., cov: 16)
Exomes π: 0.000020 ( 9 hom. )
Failed GnomAD Quality Control
Consequence
CBS
NM_000071.3 frameshift
NM_000071.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.87
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 21-43065249-CA-C is Pathogenic according to our data. Variant chr21-43065249-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188829.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065249-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CBS | NM_000071.3 | c.689del | p.Leu230ArgfsTer39 | frameshift_variant | 8/17 | ENST00000398165.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CBS | ENST00000398165.8 | c.689del | p.Leu230ArgfsTer39 | frameshift_variant | 8/17 | 1 | NM_000071.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000157 AC: 2AN: 127780Hom.: 1 Cov.: 16
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251410Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135900
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000201 AC: 26AN: 1292254Hom.: 9 Cov.: 28 AF XY: 0.0000280 AC XY: 18AN XY: 643890
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GnomAD4 genome ? AF: 0.0000157 AC: 2AN: 127780Hom.: 1 Cov.: 16 AF XY: 0.00 AC XY: 0AN XY: 61994
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Classic homocystinuria Pathogenic:3
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 11, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 21, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 26, 2023 | - - |
HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 07, 2023 | This sequence change creates a premature translational stop signal (p.Leu230Argfs*39) 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 present in population databases (rs775351239, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with homocystinuria (PMID: 21520339). ClinVar contains an entry for this variant (Variation ID: 188829). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2022 | Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 20871414, 31589614, 21520339) - |
Homocystinuria Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 06, 2023 | Variant summary: CBS c.689delT (p.Leu230ArgfsX39) 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 by our laboratory. The variant allele was found at a frequency of 4e-06 in 251410 control chromosomes (gnomAD). c.689delT has been reported in the literature in individuals affected with Homocystinuria (example: Gupta_2010 and Cozar_2011). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at