NM_000071.3:c.862G>C

Variant names:

• chr21-43063045-C-G
• rs141502207
• NM_000071.3:c.862G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM5 PP2 PP3_Strong PP5_Moderate

The NM_000071.3(CBS):​c.862G>C​(p.Ala288Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A288T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.05
• 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 11 ACMG points.

• PM1: In a strand (size 2) in uniprot entity CBS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43063045-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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, 0.993
• PP5: Variant 21-43063045-C-G is Pathogenic according to our data. Variant chr21-43063045-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1192201.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.862G>C	p.Ala288Pro	missense_variant	Exon 10 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.862G>C	p.Ala288Pro	missense_variant	Exon 10 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Homocystinuria Pathogenic:1

Jul 14, 2021

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.862G>C (p.Ala288Pro) results in a non-conservative amino acid change located in the pyridoxal-phosphate dependent enzyme domain (IPR001926) of 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 251262 control chromosomes (gnomAD). c.862G>C has been reported in the literature in a compound heterozygous individual affected with Homocystinuria (Linnebank_2004). These data do not allow any conclusion about variant significance. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated the variant to be non-functional in a yeast complementation assay (Mayfield_2012). Another missense variant affecting the same residue (A288T) was also reported in affected individuals (in HGMD and CBS database), and was found to be non-functional in in vitro studies (Mayfield_2012, and PMID 16205833), further supporting that the Ala288 residue is important for protein function. 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 likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;.;.;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;M;M;M
PhyloP100		5.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.93
MutPred		0.87		Gain of catalytic residue at A288 (P = 0.021);Gain of catalytic residue at A288 (P = 0.021);Gain of catalytic residue at A288 (P = 0.021);Gain of catalytic residue at A288 (P = 0.021);
MVP		0.91
MPC		1.3
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.98
Mutation Taster		=0/100	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

Other links and lift over

dbSNP: rs141502207; hg19: chr21-44483155;