NM_000071.3:c.622T>C

Variant names:

• chr21-43065431-A-G
• rs1060500683
• NM_000071.3:c.622T>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000071.3(CBS):​c.622T>C​(p.Trp208Arg) variant causes a missense change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W208C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 5)
  • Exomes 𝑓: 0.0000045 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 7.79
• Publications: 1 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	NM_000071.3	MANE Select	c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	NP_000062.1
	CBS	NM_001178008.3		c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	NP_001171479.1
	CBS	NM_001178009.3		c.622T>C	p.Trp208Arg	missense	Exon 7 of 18	NP_001171480.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBS	ENST00000398165.8	TSL:1 MANE Select	c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	ENSP00000381231.4
	CBS	ENST00000352178.9	TSL:1	c.622T>C	p.Trp208Arg	missense	Exon 7 of 17	ENSP00000344460.5
	CBS	ENST00000359624.7	TSL:1	c.622T>C	p.Trp208Arg	missense	Exon 7 of 18	ENSP00000352643.3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 19664 Hom.: 0 Cov.: 5

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: 0.00000400 AC: 1 AN: 249888 AF XY: 0.00

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: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000455 AC: 2 AN: 439874 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 235112

African (AFR) AF: 0.00 AC: 0 AN: 13644

American (AMR) AF: 0.00 AC: 0 AN: 30836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14778

East Asian (EAS) AF: 0.00 AC: 0 AN: 31340

South Asian (SAS) AF: 0.00 AC: 0 AN: 54406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1890

European-Non Finnish (NFE) AF: 0.00000416 AC: 1 AN: 240616

Other (OTH) AF: 0.0000409 AC: 1 AN: 24452

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 19664 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 9262

African (AFR) AF: 0.00 AC: 0 AN: 4798

American (AMR) AF: 0.00 AC: 0 AN: 2094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 534

East Asian (EAS) AF: 0.00 AC: 0 AN: 984

South Asian (SAS) AF: 0.00 AC: 0 AN: 340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 38

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 9196

Other (OTH) AF: 0.00 AC: 0 AN: 186

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Uncertain:2

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

May 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W208R variant (also known as c.622T>C), located in coding exon 5 of the CBS gene, results from a T to C substitution at nucleotide position 622. The tryptophan at codon 208 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

not provided Uncertain:1

Aug 11, 2016

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

The patient had genetic testing which included sequencing of 22 genes associated with aneurysms and dissections and related conditions: ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, FLNA, MED12, MYH11, MYLK, NOTCH1, PRKG1, SKI, SLC2A10, SMAD3, SMAD4, SMAD6, TGFB2, TGFB3, TGFBR1 and TGFBR2. Results show that no disease-causing variants were found. See report below. p.Trp208Arg (c.622T>C) in the CBS gene (NM_000090.3) The lab this variant as a variant of unknown significance. Given a lack of case data and software predictions that this variant is likely tolerated, we consider this variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been seen previously in the literature or databases of CBS DNA variants. S217F is the nearest missense variant that has been listed as pathogenic in clinvar. There are variants at 206, 204 and 212 which are listed as variants of unknown significance in clinvar. In silico analysis with PolyPhen-2 predicts the variant to be benign (HumVar: 0.010). The Trp at codon 208 is weakly conserved across species with W208Q and W208L being the alternate isoforms at that position. This variant falls in a helix domain from aa 203-213. There is variation at codon 208 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~60,000 individuals of European, African, Latino and Asian descent at this position (as of August 11, 2016). The average coverage at that site in ExAC is 30x. This individual has a Trp208Cys missense change at that position.

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Uncertain:1

Aug 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with arginine at codon 208 of the CBS protein (p.Trp208Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CBS-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	24
DANN	Benign	0.84
DEOGEN2	Pathogenic	0.87	D
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	-2.3	N
PhyloP100		7.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.60
Sift	Benign	0.74	T
Sift4G	Benign	0.61	T
Polyphen		0.0010	B
Vest4		0.87
MutPred		0.45		Gain of disorder (P = 0.0066)
MVP		0.68
MPC		0.62
ClinPred		0.32	T
GERP RS		4.7
Varity_R		0.68
gMVP		0.91
Mutation Taster		=19/81	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: rs1060500683; hg19: chr21-44485541;