rs781444670

Positions:

chr21-43066320-C-T

Variant summary

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

The ENST00000398165.8(CBS):c.374G>A(p.Arg125Gln) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125W) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 11)

Exomes 𝑓: 0.0000092 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CBS
ENST00000398165.8 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000398165.8

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-43066321-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 340089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 21-43066320-C-T is Pathogenic according to our data. Variant chr21-43066320-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 197625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066320-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant	5/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8 linkuse as main transcript	c.374G>A	p.Arg125Gln	missense_variant	5/17	1	NM_000071.3	ENSP00000381231	P1	P35520-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251098

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135818

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000922

AC:

AN:

867256

Hom.:

Cov.:

AF XY:

0.00000670

AC XY:

AN XY:

448040

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000537

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000540

Hom.:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic homocystinuria

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 14, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-05-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Apr 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 24, 2023	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 03, 2023	PP3, PM1, PM2_supporting, PM3_strong, PS3, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 125 of the CBS protein (p.Arg125Gln). This variant is present in population databases (rs781444670, gnomAD 0.005%). This missense change has been observed in individuals with homocystinuria (PMID: 7849717, 9587029, 10338090, 12124992, 21520339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197625). 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: 7849717, 20308073, 20506325, 22612060). 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

Dec 10, 2021

Variant summary: CBS c.374G>A (p.Arg125Gln) results in a non-conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926), specifically in the Cysteine synthase/cystathionine beta-synthase, pyridoxal-phosphate attachment site (IPR001216) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251098 control chromosomes. c.374G>A has been reported in the literature in multiple individuals affected with Homocystinuria (example: Marble_1994, Gaustadnes_2002, Moat_2004, Melenovska_2015, Li_2018). These data indicate that the variant is very likely to be associated with disease. At least three publications report experimental evidence evaluating an impact on protein function (example: Marble_1994, Melenovska_2015, Hnizda_2012). The most pronounced variant effect results in 2% enzymatic activity from transformed E. coli sourced protein (Marble_1994). Protein derived from CHO-K1 mammalian cells showed modest improvement at ~14% enzymatic activity (Melenovska_2015), although still less than 20% of normal wild-type CBS. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as 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

Benign

0.15

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;D;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.99

.;.;.;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

1.7

L;L;L;L;.

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

D;D;D;D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.011

D;D;D;D;T

Sift4G

Uncertain

0.015

D;D;D;D;T

Polyphen

1.0

D;D;D;D;.

Vest4

0.94

MutPred

0.88

Loss of phosphorylation at S123 (P = 0.1059);Loss of phosphorylation at S123 (P = 0.1059);Loss of phosphorylation at S123 (P = 0.1059);Loss of phosphorylation at S123 (P = 0.1059);Loss of phosphorylation at S123 (P = 0.1059);

MVP

0.94

MPC

1.1

ClinPred

0.99

GERP RS

5.3

Varity_R

0.88

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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