chr21-43062344-G-A

Variant names:

• chr21-43062344-G-A
• rs398123151
• NM_000071.3:c.1006C>T

Variant summary

Our verdict is Pathogenic. The variant received 29 ACMG points: 29P and 0B. PS1_Very_Strong PS3 PM1 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.1006C>T​(p.Arg336Cys) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000249700: Functional studies showed reduced activity of R336C in mammalian (Ismail et al., 2019) and E-coli expression systems (Urreizti et al., 2006);; SCV001467771: Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzymatic activity (see e.g. deFranchis_1999, Urreizti_2003, Urreizti_2006, Mendes_2015), in addition, recently a transgenic mouse model was also developed with mice showing marked elevation in serum homocysteine (Gupta_2019).; SCV000945559: Experimental studies have shown that this missense change affects CBS function (PMID:10408774, 16205833, 16429402, 26464485).; SCV004736288: "In vitro functional studies have shown that both p.Arg336Cys and p.Arg336His substitutions lead to decreased amount of protein and enzyme activity." PMID:16205833; PMID:16429402; PMID:22267502". Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. 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)
  • 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:13 O:1
• Conservation: PhyloP100: 8.70
• Publications: 52 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 29 ACMG points.

• PS1: Transcript NM_000071.3 (CBS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249700: Functional studies showed reduced activity of R336C in mammalian (Ismail et al., 2019) and E-coli expression systems (Urreizti et al., 2006);; SCV001467771: Multiple publications reported experimental evidence evaluating an impact on protein function, and demonstrated the lack of enzymatic activity (see e.g. deFranchis_1999, Urreizti_2003, Urreizti_2006, Mendes_2015), in addition, recently a transgenic mouse model was also developed with mice showing marked elevation in serum homocysteine (Gupta_2019).; SCV000945559: Experimental studies have shown that this missense change affects CBS function (PMID: 10408774, 16205833, 16429402, 26464485).; SCV004736288: "In vitro functional studies have shown that both p.Arg336Cys and p.Arg336His substitutions lead to decreased amount of protein and enzyme activity." PMID:16205833; PMID:16429402; PMID:22267502
• 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, 0.992
• PP5: Variant 21-43062344-G-A is Pathogenic according to our data. Variant chr21-43062344-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 92423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000071.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 11 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.1006C>T	p.Arg336Cys	missense	Exon 11 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.1006C>T	p.Arg336Cys	missense	Exon 11 of 18	NP_001171480.1	P35520-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.1006C>T	p.Arg336Cys	missense	Exon 11 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.1006C>T	p.Arg336Cys	missense	Exon 11 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.1006C>T	p.Arg336Cys	missense	Exon 11 of 18	ENSP00000352643.3	P35520-1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250690 AF XY: 0.0000147

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: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2302 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1212

African (AFR) AF: 0.00 AC: 0 AN: 202

American (AMR) AF: 0.00 AC: 0 AN: 484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 32

East Asian (EAS) AF: 0.00 AC: 0 AN: 220

South Asian (SAS) AF: 0.00 AC: 0 AN: 130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080

Other (OTH) AF: 0.00 AC: 0 AN: 128

GnomAD4 genome Cov.: 0

Alfa AF: 0.0000365 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Classic homocystinuria (8)
3	-	-	not provided (3)
1	-	-	CBS-related disorder (1)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H
PhyloP100		8.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MVP		0.94
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.96
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs398123151; hg19: chr21-44482454;