rs121964963

Positions:

• chr21-43066260-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):​c.434C>T​(p.Pro145Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 16)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.69

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-43066260-G-A is Pathogenic according to our data. Variant chr21-43066260-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43066260-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.434C>T	p.Pro145Leu	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	c.434C>T	p.Pro145Leu	missense_variant	5/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249936 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135344

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1214644 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 608286

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 16

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Sep 18, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -

Homocystinuria Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 01, 2024	Variant summary: CBS c.434C>T (p.Pro145Leu) results in a non-conservative amino acid change located in the Tryptophan synthase beta chain-like, PALP domain (IPR001926) 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 4e-06 in 249936 control chromosomes. c.434C>T has been reported in the literature in multiple homozygous or compound heterozygous individuals affected with Homocystinuria (Kozich_1993, Urreizti_2006, Karaca_2014, Alcaide_2015). These data indicate that the variant is very 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 residual enzymatic activity and nonfunctional yeast cells in yeat growth assays (Mayfield_2012). The following publications have been ascertained in the context of this evaluation (PMID: 25218699, 24211323, 8353501, 22267502, 16479318). ClinVar contains an entry for this variant (Variation ID: 118). Based on the evidence outlined above, the variant was classified as pathogenic. -

Homocystinuria, pyridoxine-responsive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 1993

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 145 of the CBS protein (p.Pro145Leu). This variant is present in population databases (rs121964963, gnomAD 0.006%). This missense change has been observed in individual(s) with homocystinuria (PMID: 8353501, 16479318, 24211323, 25218699). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 118). 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: 8353501, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	.;.;.;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	M;M;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-9.6	D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.91
MutPred		0.94		Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);Loss of disorder (P = 0.0377);
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.96

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

Other links and lift over

dbSNP: rs121964963; hg19: chr21-44486370;