rs775992753

Variant names:

• chr21-43066333-G-A
• rs775992753
• NM_000071.3:c.361C>T

Your query was ambiguous. Multiple possible variants found:

• chr21-43066333-G-A
• chr21-43066333-G-C

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.361C>T​(p.Arg121Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. R121G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 9)
  • Exomes 𝑓: 0.000035 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 3.43
• Publications: 5 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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43066333-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2913713.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 21-43066333-G-A is Pathogenic according to our data. Variant chr21-43066333-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 212842.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.361C>T	p.Arg121Cys	missense_variant	Exon 5 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.361C>T	p.Arg121Cys	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 9

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251102 AF XY: 0.0000295

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000352 AC: 28 AN: 794602 Hom.: 2 Cov.: 11 AF XY: 0.0000315 AC XY: 13 AN XY: 412208

African (AFR) AF: 0.00 AC: 0 AN: 14384

American (AMR) AF: 0.00 AC: 0 AN: 40338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19304

East Asian (EAS) AF: 0.00 AC: 0 AN: 36566

South Asian (SAS) AF: 0.00 AC: 0 AN: 67576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2968

European-Non Finnish (NFE) AF: 0.0000517 AC: 28 AN: 542108

Other (OTH) AF: 0.00 AC: 0 AN: 37136

GnomAD4 genome Cov.: 9

Alfa AF: 0.000183 Hom.: 0

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:2

Apr 23, 2018

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CBS c.361C>T (p.Arg121Cys) missense variant has been reported in three studies in which it is identified in a homozygous state in one individual and in a compound heterozygous state in a second individual in trans with a known pathogenic variant, both diagnosed with CBS deficiency (Katushima et al. 2006; Cozar et al. 2011). The variant has also been reported in a compound heterozygous state in one individual described as asymptomatic and in an additional two patient alleles of unknown zygosity (Kraus et al. 1999). In one study, the p.Arg121Cys variant was absent from 100 ethnically matched control chromosomes but is reported at a frequency of 0.000060 in the European (non-Finnish) population of the Exome Aggregation Consortium. Contradictory results were obtained in functional studies in yeast: Wei et al. (2010) describe the variant as neutral whereas Mayfield et al. (2012) describe the variant as non-functional. Six prediction algorithms predict the variant to be deleterious (Wei et al. 2010). The Arg121 residue is conserved and involved in important salt-bridge interactions with other residues (Wei et al. 2010). Based on the evidence, the p.Arg121Cys variant is classified as likely pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Nov 27, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Jun 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 121 of the CBS protein (p.Arg121Cys). This variant is present in population databases (rs775992753, gnomAD 0.004%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 21520339; Invitae). ClinVar contains an entry for this variant (Variation ID: 212842). 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: 22267502). This variant disrupts the p.Arg121 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10338090, 22267502, 22353391). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Oct 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); The p.(R121C) variant was determined to be nonfunctional in yeast complementation studies (Mayfield et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20455263, 10338090, 21520339, 16307898, 12686134, 22267502) -

Homocystinuria Pathogenic:1

Apr 14, 2022

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.361C>T (p.Arg121Cys) 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 allele was found at a frequency of 1.6e-05 in 251102 control chromosomes (gnomAD). The variant, c.361C>T, has been reported in the literature in individuals affected with Homocystinuria, including one homozygote (Kraus_1999, Katsushima_2006, Cozar_2011). These data indicate that the variant is likely to be associated with disease. One publication, (Mayfield_2012), tested the function of this variant in a yeast assay and reported the variant to be non-functional, while a different functional study, also using a yeast assay, reported the variant as neutral (Wei_2010). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D;D;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;H;H;H;.
PhyloP100		3.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.0	D;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.98
MutPred		0.99		Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);Gain of catalytic residue at S123 (P = 0.0362);
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.97
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

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: rs775992753; hg19: chr21-44486443;