rs1555874874

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PP2PP3_StrongPP5_Moderate

The NM_000071.3(CBS):​c.650C>T​(p.Ser217Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 5)

Consequence

CBS
NM_000071.3 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 8.36

Publications

0 publications found
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]
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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 107 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Gene score misZ: 0.8318 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to classic homocystinuria.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.991
PP5
Variant 21-43065403-G-A is Pathogenic according to our data. Variant chr21-43065403-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 557413.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CBSNM_000071.3 linkc.650C>T p.Ser217Phe missense_variant Exon 7 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.650C>T p.Ser217Phe missense_variant Exon 7 of 17 1 NM_000071.3 ENSP00000381231.4 P35520-1

Frequencies

GnomAD3 genomes
Cov.:
5
GnomAD4 exome
Cov.:
5
GnomAD4 genome
Cov.:
5

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Homocystinuria Pathogenic:1
Mar 31, 2025
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.650C>T (p.Ser217Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250464 control chromosomes. c.650C>T has been reported in the literature in the compound heterozygous state in an individual affected with Homocystinuria (Katsushima_2006). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <5% activity versus the WT protein, reduced activation in response to S-Adenosylmethionine, and the absence of a correctly assembled tetramer detected by Western blot (Katsushima_2006). The following publication have been ascertained in the context of this evaluation (PMID: 16307898). ClinVar contains an entry for this variant (Variation ID: 557413). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Classic homocystinuria Uncertain:1
Mar 30, 2018
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;D;D;D
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
.;.;.;D
M_CAP
Pathogenic
0.89
D
MetaRNN
Pathogenic
0.99
D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;M;M;M
PhyloP100
8.4
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-5.2
D;D;D;D
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0
D;D;D;D
Vest4
0.78
MutPred
0.93
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
0.94
MPC
1.2
ClinPred
0.98
D
GERP RS
4.7
Varity_R
0.97
gMVP
0.91
Mutation Taster
=1/99
disease causing

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

Other links and lift over

dbSNP: rs1555874874; hg19: chr21-44485513; API