NM_000071.3:c.361C>T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 21 ACMG points: 21P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000249677: The p.(R121C) variant was determined to be nonfunctional in yeast complementation studies (Mayfield et al., 2021)" and additional evidence is available in ClinVar. 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet, Myriad Women’s Health, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 21 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000249677: The p.(R121C) variant was determined to be nonfunctional in yeast complementation studies (Mayfield et al., 2021); SCV000436228: 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.; SCV001361017: 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).; SCV000543501: Experimental studies have shown that this missense change affects CBS function (PMID: 22267502).
• 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.

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.361C>T	p.Arg121Cys	missense	Exon 5 of 17	NP_000062.1	P35520-1
	CBS	NM_001178008.3		c.361C>T	p.Arg121Cys	missense	Exon 5 of 17	NP_001171479.1	P35520-1
	CBS	NM_001178009.3		c.361C>T	p.Arg121Cys	missense	Exon 5 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.361C>T	p.Arg121Cys	missense	Exon 5 of 17	ENSP00000381231.4	P35520-1
	CBS	ENST00000352178.9	TSL:1	c.361C>T	p.Arg121Cys	missense	Exon 5 of 17	ENSP00000344460.5	P35520-1
	CBS	ENST00000359624.7	TSL:1	c.361C>T	p.Arg121Cys	missense	Exon 5 of 18	ENSP00000352643.3	P35520-1

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

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Classic homocystinuria (2)
1	-	-	Homocystinuria (1)
1	-	-	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.8	H
PhyloP100		3.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-8.0	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.99		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;