rs763835246

Positions:

• chr21-43065263-C-T
• chr21-43065263-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000071.3(CBS):​c.676G>A​(p.Ala226Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 2.70

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 21-43065263-C-T is Pathogenic according to our data. Variant chr21-43065263-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065263-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.676G>A	p.Ala226Thr	missense_variant	8/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.676G>A	p.Ala226Thr	missense_variant	8/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.81e-7 AC: 1 AN: 1280734 Hom.: 0 Cov.: 27 AF XY: 0.00000157 AC XY: 1 AN XY: 638702

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000105

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 15

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Child Health and Human Development Program, Research Institute of the McGill University Health Center	-	The c.676G>A (A226T) was identified in a patients of French Canadian origin in compound heterozygote with c.313C>G (L105V). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had no intellectual impairment and responds to treatment with vitamin B6. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 04, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 29, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.676G>A;p.(Ala226Thr) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 370382; PMID: 14635102; 21520339; 15365998; 16429402; 9590298) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 22267502, 21520339, 20066033, 17540596) - PS3_moderate. The variant is located in a mutational hot spot and/or critical and well-established functional domain (PALP domain) - PM1. This variant is not present in population databases (rs763835246, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The p.(Ala226Thr) was detected homozygous state in analyzed sample and was observed in trans with a pathogenic variant (PMID: 21520339; 14635102)PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 226 of the CBS protein (p.Ala226Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with homocystinuria (PMID: 14635102, 15365998, 21520339). ClinVar contains an entry for this variant (Variation ID: 370382). 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. Experimental studies have shown that this missense change affects CBS function (PMID: 9590298, 14635102, 16429402, 17540596, 20066033, 22267502). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 04, 2023

Functional analysis of p.(A226T) variant is associated with significantly reduced enzyme activity (Urreizti et al., 2006; Kruger et al., 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21520339, 22267502, 14635102, 17540596, 16479318, 31589614, 16429402) -

Homocystinuria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 06, 2021

Variant summary: CBS c.676G>A (p.Ala226Thr) results in a non-conservative amino acid change located in the Pryridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251378 control chromosomes. c.676G>A has been reported in the literature in individuals affected with mild Homocystinuria who are responsive to treatment with Pyridoxine (Vitamin-B6) (example, Kruger_2003, Linnebank_2004, Cozar_2011). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal CBS enzyme activity (example, Kruger_2003, Urreizti_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic citing overlapping evidence utilized in the context of this evaluation. 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	Benign	0.10
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;D;D;D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.033
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.97	.;.;.;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	0.71	N;N;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.020	D;D;D;D
Sift4G	Benign	0.074	T;T;T;T
Polyphen		0.10	B;B;B;B
Vest4		0.41
MutPred		0.82		Gain of glycosylation at A226 (P = 0.0447);Gain of glycosylation at A226 (P = 0.0447);Gain of glycosylation at A226 (P = 0.0447);Gain of glycosylation at A226 (P = 0.0447);
MVP		0.76
MPC		0.39
ClinPred		0.59	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.68

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: rs763835246; hg19: chr21-44485373;