21-43072174-TG-TGG

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000071.3(CBS):​c.19dupC​(p.Gln7ProfsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: not found (cov: 0)

Consequence

CBS
NM_000071.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 0.0790
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 172 pathogenic variants in the truncated region.
PP5
Variant 21-43072174-T-TG is Pathogenic according to our data. Variant chr21-43072174-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 371345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBSNM_000071.3 linkc.19dupC p.Gln7ProfsTer30 frameshift_variant Exon 3 of 17 ENST00000398165.8 NP_000062.1 P35520-1Q9NTF0

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CBSENST00000398165.8 linkc.19dupC p.Gln7ProfsTer30 frameshift_variant Exon 3 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
Cov.:
0
GnomAD3 exomes
AF:
0.00000411
AC:
1
AN:
243178
Hom.:
0
AF XY:
0.00000752
AC XY:
1
AN XY:
132972
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000547
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
0
GnomAD4 genome
Cov.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Classic homocystinuria Pathogenic:5
Mar 15, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 02, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 05, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 14, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1
Jan 04, 2024
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.Gln7Profs*30) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with CBS deficiency (PMID: 10338090, 12124992). ClinVar contains an entry for this variant (Variation ID: 371345). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1
May 31, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10338090, 31589614, 25218699) -

CBS-related disorder Pathogenic:1
Jul 01, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The CBS c.19dupC variant is predicted to result in a frameshift and premature protein termination (p.Gln7Profs*30). This variant has been reported in both the homozygous and compound heterozygous states in multiple individuals with homocystinuria (referred to as 19insC in Kraus et al. 1999. PubMed ID: 10338090; Gaustadnes et al. 2002. PubMed ID: 12124992; Janosík et al. 2001. PubMed ID: 11359213; Alcaide et al. 2014. PubMed ID: 25218699). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD. Frameshift variants in CBS are expected to be pathogenic. This variant is interpreted as pathogenic. -

Homocystinuria Pathogenic:1
Apr 26, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CBS c.19dupC (p.Gln7ProfsX30) 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. The variant allele was found at a frequency of 4.1e-06 in 243178 control chromosomes (gnomAD). c.19dupC has been reported in the literature in multiple homozygote and compound heterozygote individuals affected with Homocystinuria (Alcaide_2015, Gaustadnes_2002). These data indicate that the variant is very likely to be associated with disease. A compound heterozygote affected individual was found to have <10% CBS activity (Alcaide_2015). Three ClinVar submisions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748695461; hg19: chr21-44492284; API