chr21-43062343-C-G

Variant names:

• chr21-43062343-C-G
• rs760417941
• NM_000071.3:c.1007G>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.1007G>C​(p.Arg336Pro) variant causes a missense change. In-silico tool predicts a pathogenic 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. R336L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 6.85
• Publications: 0 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 0 benign, 7 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062343-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2908236.
• 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 21-43062343-C-G is Pathogenic according to our data. Variant chr21-43062343-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1052953.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.1007G>C	p.Arg336Pro	missense_variant	Exon 11 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1007G>C	p.Arg336Pro	missense_variant	Exon 11 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Aug 04, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R336P variant (also known as c.1007G>C), located in coding exon 9 of the CBS gene, results from a G to C substitution at nucleotide position 1007. The arginine at codon 336 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported as compound heterozygous with a known pathogenic mutation in CBS in an individual with homocystinuria (Ambry internal data). Another alteration at the same codon, p.R336H (c.1007G>A), has been detected as homozygous in two family members with homocystinuria (Coudé M et al. J Inherit Metab Dis, 1998 Dec;21:823-8), and showed an impact on enzyme activity in functional studies (Urreizti R et al. Hum Mutat, 2006 Feb;27:211; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Mendes MI et al. Hum Mol Genet, 2015 Dec;24:7339-48). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Sep 05, 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 proline, which is neutral and non-polar, at codon 336 of the CBS protein (p.Arg336Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CBS deficiency (internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1052953). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CBS protein function with a positive predictive value of 95%. This variant disrupts the p.Arg336 amino acid residue in CBS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10408774, 12815602, 16205833, 16429402, 21517828, 26464485). 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. -

Classic homocystinuria Uncertain:1

Apr 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	.;.;.;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;H
PhyloP100		6.8
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.9	D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.85		Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);Loss of stability (P = 0.0765);
MVP		0.94
MPC		1.4
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.99
gMVP		0.99
Mutation Taster		=0/100	disease causing

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: rs760417941; hg19: chr21-44482453;