21-43066332-C-T

Variant names:

• chr21-43066332-C-T
• rs770095972
• NM_000071.3:c.362G>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.362G>A​(p.Arg121His) variant causes a missense change. 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: 𝑓 0.0 (0 hom., cov: 9)
  • Exomes 𝑓: 0.0000088 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.84
• Publications: 9 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, 0.95
• PP5: Variant 21-43066332-C-T is Pathogenic according to our data. Variant chr21-43066332-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188948.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.362G>A	p.Arg121His	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.362G>A	p.Arg121His	missense_variant	Exon 5 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 74826 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251070 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000185

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000885 AC: 7 AN: 791080 Hom.: 0 Cov.: 11 AF XY: 0.0000146 AC XY: 6 AN XY: 410534

African (AFR) AF: 0.0000699 AC: 1 AN: 14304

American (AMR) AF: 0.0000249 AC: 1 AN: 40238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19252

East Asian (EAS) AF: 0.00 AC: 0 AN: 36494

South Asian (SAS) AF: 0.00 AC: 0 AN: 67460

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2970

European-Non Finnish (NFE) AF: 0.00000556 AC: 3 AN: 539176

Other (OTH) AF: 0.0000270 AC: 1 AN: 36982

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 74826 Hom.: 0 Cov.: 9 AF XY: 0.00 AC XY: 0 AN XY: 35968

African (AFR) AF: 0.00 AC: 0 AN: 11194

American (AMR) AF: 0.00 AC: 0 AN: 8862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2026

East Asian (EAS) AF: 0.00 AC: 0 AN: 3676

South Asian (SAS) AF: 0.00 AC: 0 AN: 2280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 142

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 39382

Other (OTH) AF: 0.00 AC: 0 AN: 998

Alfa AF: 0.0000617 Hom.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:3

Nov 03, 2021

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000071.2(CBS):c.362G>A(R121H) is a missense variant classified as likely pathogenic in the context of homocystinuria, CBS-related. R121H has been observed in cases with relevant disease (PMID: 10338090, 16307898, 16479318, 30873612). Functional assessments of this variant are available in the literature (PMID: 16307898, 22267502). R121H has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000071.2(CBS):c.362G>A(R121H) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jun 22, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R121H pathogenic mutation (also known as c.362G>A), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 362. The arginine at codon 121 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in the homozygous and compound heterozygous states with other alterations in CBS in several individuals with homocystinuria, features of homocystinuria and/or CBS-deficiency (Kraus JP et al. Hum Mutat, 1999;13:362-75; Urreizti R et al. J Hum Genet, 2006 Feb;51:305-313; Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8; Van Hove JLK et al. J Inherit Metab Dis, 2019 05;42:424-437). In expression studies in E. coli, this variant showed decreased enzyme activity and impaired capability to correctly form tetramers (Katsushima F et al. Mol Genet Metab, 2006 Apr;87:323-8). In a yeast growth assay, this variant was characterized as nonfunctional (Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Jun 03, 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 histidine, which is basic and polar, at codon 121 of the CBS protein (p.Arg121His). This variant is present in population databases (rs770095972, gnomAD 0.03%). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 16307898, 16479318). ClinVar contains an entry for this variant (Variation ID: 188948). 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: 16307898, 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, 16307898, 21520339; Invitae). 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. -

Homocystinuria Pathogenic:1

Aug 31, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CBS c.362G>A (p.Arg121His) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain 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 2.4e-05 in 251070 control chromosomes. c.362G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example, Katsushima_2006, Urreizti_2006, Kraus_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severely impaired enzyme activity resulting from impaired tetramer assembly (Katsushima_2006). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. 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	0.36	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D;D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H;H;H;H;.
PhyloP100		6.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Pathogenic	0.96
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		0.96
MVP		0.95
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.97
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: rs770095972; hg19: chr21-44486442; COSMIC: COSV61442706; COSMIC: COSV61442706;