rs779270933

chr21-43063003-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000071.3(CBS):c.904G>A(p.Glu302Lys) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E302E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 6.85

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in NM_000071.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 21-43063003-C-T is Pathogenic according to our data. Variant chr21-43063003-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496864.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Likely_pathogenic=1, Uncertain_significance=1}. Variant chr21-43063003-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.904G>A	p.Glu302Lys	missense_variant	10/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.904G>A	p.Glu302Lys	missense_variant	10/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135892

Gnomad AFR exome AF: 0.0000615

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 28, 2022

- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 08, 2023

This variant is present in population databases (rs779270933, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 302 of the CBS protein (p.Glu302Lys). This missense change has been observed in individuals with homocystinuria (PMID: 10338090, 12124992, 29326875; Invitae). ClinVar contains an entry for this variant (Variation ID: 496864). 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. Experimental studies have shown that this missense change affects CBS function (PMID: 10338090, 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Homocystinuria Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Dec 15, 2021

Variant summary: CBS c.904G>A (p.Glu302Lys) results in a conservative amino acid change located in the Pyridoxal-phosphate dependent enzyme domain (IPR001926) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. c.904G>A has been reported in the literature as a compound heterozygous genotype in individuals affected with Homocystinuria (example, Kraus_1999, Gaustadnes_2002, Voskoboeva_2018). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function (example, deFranchis_1999, Kozich_2010, Mayfield_2012). The most pronounced variant effect results in 4.9% of normal CBS enzyme activity when expressed in Ecoli extracts and a shorter than expected subunit size by western blot analysis suggestive of partial degradation of the mutant enzyme (deFranchis_1999), inhibited by AdoHcy and not activated by AdoMet (Kozich_2010), and a nonfunctional outcome in yeast as measured by ortholog replacement in Saccharomyces cerevisiae (Mayfield_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic and one laboratory classified the variant as uncertain significance. One submitter cites overlapping evidence utilized in the context of this evalution. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.045
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.95	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	-0.97	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Pathogenic	0.71
Sift	Benign	0.45	T;T;T;T
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.41	B;B;B;B
Vest4		0.93
MutPred		0.81		Gain of methylation at E302 (P = 0.0082);Gain of methylation at E302 (P = 0.0082);Gain of methylation at E302 (P = 0.0082);Gain of methylation at E302 (P = 0.0082);
MVP		0.72
MPC		0.62
ClinPred		0.58	D
GERP RS		4.7
Varity_R		0.65
gMVP		0.90

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

Other links and lift over

dbSNP: rs779270933; hg19: chr21-44483113;