rs1347651454

chr21-43065653-C-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.494G>A(p.Cys165Tyr) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C165G) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 6.78

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43065654-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 580466.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 21-43065653-C-T is Pathogenic according to our data. Variant chr21-43065653-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 495531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43065653-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.494G>A	p.Cys165Tyr	missense_variant	6/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.494G>A	p.Cys165Tyr	missense_variant	6/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000544 AC: 1 AN: 183760 Hom.: 0 AF XY: 0.0000102 AC XY: 1 AN XY: 98334

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 290772 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 153218

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2016

The p.C165Y pathogenic mutation (also known as c.494G>A), located in coding exon 4 of the CBS gene, results from a G to A substitution at nucleotide position 494. The cysteine at codon 165 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been previously reported as detected in the homozygous state and compound heterozygous state with other mutations in individuals with CBS deficiency or homocystinuria (Kluijtmans LA et al. Hum Genet. 1995;96:249-50; Kluijtmans LA et al. Am J Hum Genet. 1999;65(1):59-67; Janosík M et al. Am J Hum Genet. 2001;68:1506-13; Gaustadnes M et al. Hum Mutat. 2002;20:117-26; Magner M et al. J Inherit Metab Dis. 2011;34:33-7; Mayfield JA et al. Genetics. 2012;190:1309-23). In addition, fibroblasts derived from patients homozygous for this alteration have deficient CBS activity, and this variant results in reduced enzyme activity in multiple other in vitro studies (Gordon RB et al. Hum Mutat. 1998;11:332; Kluijtmans LA et al. Am J Hum Genet. 1999;65(1):59-67; Janosík M et al. Am J Hum Genet. 2001;68:1506-13; Mayfield JA et al. Genetics. 2012;190:1309-23; Melenovská P et al. J Inherit Metab Dis. 2015;38:287-94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 16, 2021

ACMG categories: PS3,PM1,PM2,PP1,PP3,PP5 -

Classic homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 07, 2023

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 165 of the CBS protein (p.Cys165Tyr). 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 missense change has been observed in individual(s) with homocystinuria (PMID: 7635485, 10215408, 10364517, 12124992, 18708589, 20567906). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 495531). 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: 10215408, 11359213, 20490928, 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 24, 2017

Variant summary: The CBS c.494G>A (p.Cys165Tyr) variant causes a missense change involving the alteration of a conserved nucleotide located in the Tryptophan synthase beta subunit-like PLP-dependent enzyme domain.. 5/5 in silico tools predict a damaging outcome for this variant. An enzymatic assay using yeast showed non-functional CBS enzyme associated with this variant (Mayfield_2012), and in at least one patient homozygous for the variant, activity in fibroblasts was non-detectable (Kluijtmans_1999). This variant was not found in the large control database ExAC in 29004 control chromosomes and was reported in multiple patients with homocystinuria (Kluijtmans_1999, Magner_2011). Taken together, this variant is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M;M;M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-9.8	D;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.96
MVP		0.93
MPC		1.5
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.96

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: rs1347651454; hg19: chr21-44485763;