rs745704046

Variant names:

• chr21-43065690-C-T
• rs745704046
• NM_000071.3:c.457G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PP2 PP3_Strong PP5

The NM_000071.3(CBS):​c.457G>A​(p.Gly153Arg) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.000012 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:1
• Conservation: PhyloP100: 5.09
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000071.3
• 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, 0.987
• PP5: Variant 21-43065690-C-T is Pathogenic according to our data. Variant chr21-43065690-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212846.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.457G>A	p.Gly153Arg	missense_variant	Exon 6 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.457G>A	p.Gly153Arg	missense_variant	Exon 6 of 17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD2 exomes AF: 0.00000612 AC: 1 AN: 163370 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: 0.0000154

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000119 AC: 3 AN: 253030 Hom.: 1 Cov.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 133912

African (AFR) AF: 0.00 AC: 0 AN: 7730

American (AMR) AF: 0.00 AC: 0 AN: 13060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6884

East Asian (EAS) AF: 0.00 AC: 0 AN: 19994

South Asian (SAS) AF: 0.0000516 AC: 2 AN: 38768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13716

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1000

European-Non Finnish (NFE) AF: 0.00000725 AC: 1 AN: 137896

Other (OTH) AF: 0.00 AC: 0 AN: 13982

GnomAD4 genome Cov.: 0

ExAC AF: 0.00000874 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:3 Uncertain:1

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly153Arg variant in CBS has been reported in 1 individual severe hyperhomocysteinemia which was compound heterozygous with a pathogenic variant, and in 1 homozygous individual with homocystinuria which segregatred in an affected sibling (An 2013 PMID: 30246729, aidi 2012 PMID: 21517828). Biochemical examination in these individuals showed high plasma homocysteine levels (An 2013 PMID: 30246729, aidi 2012 PMID: 21517828), and in vitro functional studies support an impact to the protein (Mayfield 2012 PMID 22267502). The variant was absent in large population databases. It was reported in ClinVar (Variation ID 212846). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homcystinuria. ACMG/AMP criteria applied: PM3, PS3, PM2_Supporting, PP1, PP3, PP4.

Nov 19, 2021

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000071.2(CBS):c.457G>A(G153R) is a missense variant classified as a variant of uncertain significance in the context of homocystinuria, CBS-related. G153R has been observed in cases with relevant disease (PMID: 21517828, 16167124, 30246729). Functional assessments of this variant are available in the literature (PMID: 20455263, 22267502, 32000841). G153R has been observed in population frequency databases (gnomAD: NFE <0.002%). In summary, there is insufficient evidence to classify NM_000071.2(CBS):c.457G>A(G153R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

Apr 01, 2023

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 10, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Nov 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 153 of the CBS protein (p.Gly153Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of CBS-related conditions (PMID: 21517828, 30246729). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 212846). 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: 22267502; external communication). For these reasons, this variant has been classified as Pathogenic.

not provided Pathogenic:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CBS: PM2, PM3, PP4:Moderate, PP3, PS3:Supporting

Homocystinuria Pathogenic:1

Nov 09, 2017

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CBS c.457G>A (p.Gly153Arg) variant involves the alteration of a conserved nucleotide that lies within the pyridoxal-phosphate dependent enzyme domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 1/156632 control chromosomes at a frequency of 0.0000064, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). The variant has been reported in a Saudi Arabian family, where two affected patients were homozygous for the variant, which was inherited from unaffected consanguineous heterozygous parents (Zaidi_2012). Additionally, two functional studies in yeast suggest that the variant may impact protein function (Wei_2010, Mayfield_2012). Taken together, this variant is classified as likely pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	1.0	D;D;D;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.68
LIST_S2	Benign	0.0	.;.;.;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.6	H;H;H;H;.
PhyloP100		5.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-7.9	D;D;D;D;D
Sift	Uncertain	0.0090	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Vest4		0.90
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs745704046; hg19: chr21-44485800; COSMIC: COSV61441297; COSMIC: COSV61441297;