rs777919630

Variant names:

• chr21-43062358-G-A
• rs777919630
• NM_000071.3:c.992C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43062358-G-A
• chr21-43062358-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.992C>T​(p.Ala331Val) 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. A331E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a helix (size 14) in uniprot entity CBS_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062358-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-43062358-G-A is Pathogenic according to our data. Variant chr21-43062358-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 193793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062358-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.992C>T	p.Ala331Val	missense_variant	Exon 11 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.992C>T	p.Ala331Val	missense_variant	Exon 11 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250866 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135762

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

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: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:2

Mar 18, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.992C>T(p.Ala331Val) in CBS gene has been reported previously in homozygous state in individuals affected with Thrombosis, hyperhomocysteinemic (Kaur R et. al., 2020). Experimental studies have shown that this missense change affects CBS function (Mayfield et al., 2012). This variant is reported with the allele frequency of 0.0008% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance / Likely Pathogenic. The amino acid Ala at position 331 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ala331Val in CBS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT -Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. This variant has been partially explaining the phenotype. For these reasons, the variant has been classified as Likely Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 31, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A331V variant (also known as c.992C>T), located in coding exon 9 of the CBS gene, results from a C to T substitution at nucleotide position 992. The alanine at codon 331 is replaced by valine, an amino acid with similar properties. This alteration has been reported as homozygous in two siblings with homocystinuria (Kaur R et al. Sci Rep, 2020 Oct;10:17299). Based on internal structural analysis, this alteration is deleterious, being moderately destabilizing to the local structure (Kruger WD et al. Hum Mutat. 2003 Dec;22(6):434-41). Additionally, in vitro assays showed this alteration has residual protein function (Kruger WD et al. Hum Mol Genet, 1995 Jul;4:1155-61; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Dec 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 331 of the CBS protein (p.Ala331Val). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of homocystinuria (PMID: 33057012). ClinVar contains an entry for this variant (Variation ID: 193793). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects CBS function (PMID: 8528202, 22267502). This variant disrupts the p.Ala331 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9156316; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not provided Uncertain:1

Nov 20, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability Uncertain:1

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;.;.;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.9	D;D;D;D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.94	P;P;P;P
Vest4		0.88
MutPred		0.93		Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.88
MPC		0.53
ClinPred		0.88	D
GERP RS		5.2
Varity_R		0.47
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs777919630; hg19: chr21-44482468;