rs1347651454

Variant names:

• chr21-43065653-C-T
• rs1347651454
• NM_000071.3:c.494G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM5 PP2 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
• Publications: 10 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 17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 VariationId is 580466.Status of the report is criteria_provided_single_submitter, 1 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, 0.985
• PP5: Variant 21-43065653-C-T is Pathogenic according to our data. Variant chr21-43065653-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 495531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.494G>A	p.Cys165Tyr	missense_variant	Exon 6 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.494G>A	p.Cys165Tyr	missense_variant	Exon 6 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000544 AC: 1 AN: 183760 AF XY: 0.0000102

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 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

African (AFR) AF: 0.00 AC: 0 AN: 8950

American (AMR) AF: 0.00 AC: 0 AN: 14342

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8230

East Asian (EAS) AF: 0.00 AC: 0 AN: 24574

South Asian (SAS) AF: 0.00 AC: 0 AN: 40310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 16852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1212

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 159808

Other (OTH) AF: 0.00 AC: 0 AN: 16494

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

Oct 26, 2016

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 16, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Classic homocystinuria Pathogenic:1

Sep 07, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Aug 24, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Pathogenic	0.98	.;.;.;D;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;.
PhyloP100		6.8
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
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
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: rs1347651454; hg19: chr21-44485763;