rs755952006

Positions:

chr21-43066252-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000071.3(CBS):c.442G>A(p.Gly148Arg) 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. G148A) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., cov: 16)

Exomes 𝑓: 0.0000090 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CBS
NM_000071.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.84

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000071.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066251-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1980875.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 21-43066252-C-T is Pathogenic according to our data. Variant chr21-43066252-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066252-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.442G>A	p.Gly148Arg	missense_variant	5/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.442G>A	p.Gly148Arg	missense_variant	5/17	1	NM_000071.3	P1	P35520-1

Frequencies

GnomAD3 genomes

AF:

0.00000879

AC:

AN:

113824

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000776

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249522

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135182

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000898

AC:

AN:

1225432

Hom.:

Cov.:

AF XY:

0.00000979

AC XY:

AN XY:

613004

show subpopulations

Gnomad4 AFR exome

AF:

0.000107

Gnomad4 AMR exome

AF:

0.0000236

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000859

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000879

AC:

AN:

113824

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

55462

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000776

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000303

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 15, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 22, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 10, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2020

The p.G148R variant (also known as c.442G>A), located in coding exon 3 of the CBS gene, results from a G to A substitution at nucleotide position 442. The glycine at codon 148 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported as homozygous and as a compound heterozygote in subjects with features of homocystinuria (Kraus JP et al. Hum Mutat, 1999;13:362-75; Orendáè M et al. Hum Mutat, 2004 Jun;23:631). This alteration has also been shown to have an impact on protein function (Meier M et al. Biochim Biophys Acta, 2003 Apr;1647:206-13; Orendáè M et al. Hum Mutat, 2004 Jun;23:631; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23). 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2023

Published functional studies demonstrate a damaging effect: decreased enzyme activity and failure to restore function /rescue growth when expressed in a yeast system lacking the CBS ortholog (Kozich et al., 2010; Mayfield et al., 2012; Melenovska et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20490928, 25331909, 20506325, 20694756, 22267502, 10338090, 16307898, 16429402, 16479318, 15146473) -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 148 of the CBS protein (p.Gly148Arg). This variant is present in population databases (rs755952006, gnomAD 0.007%). This missense change has been observed in individual(s) with homocystinuria due to CBS deficiency (PMID: 15146473, 16307898, 16479318, 20694756). ClinVar contains an entry for this variant (Variation ID: 371512). 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: 16307898, 16429402, 20490928, 20506325). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 31, 2019

Variant summary: The variant, CBS c.442G>A (p.Gly148Arg) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244468 control chromosomes (gnomAD). The variant,c.442G>A has been reported in the literature in individuals affected with Homocystinuria (Katsushima_2005, Orendac_2004, Urreizti_2006). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Kozich_2010, Katsushima_2005, Orendac_2004). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.88

LIST_S2

Pathogenic

1.0

.;.;.;D;D

M_CAP

Pathogenic

0.93

MetaRNN

Pathogenic

1.0

D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.8

H;H;H;H;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-8.0

D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.99

MutPred

1.0

Gain of MoRF binding (P = 0.078);Gain of MoRF binding (P = 0.078);Gain of MoRF binding (P = 0.078);Gain of MoRF binding (P = 0.078);Gain of MoRF binding (P = 0.078);

MVP

0.94

MPC

1.2

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over