chr21-43063976-A-G

Position:

• chr21-43063976-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_Strong PP5

The NM_000071.3(CBS):​c.752T>C​(p.Leu251Pro) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 3)
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 8.10

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983
• PP5: Variant 21-43063976-A-G is Pathogenic according to our data. Variant chr21-43063976-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 555482.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.752T>C	p.Leu251Pro	missense_variant	9/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.752T>C	p.Leu251Pro	missense_variant	9/17	1	NM_000071.3	ENSP00000381231.4

Frequencies

GnomAD3 genomes Cov.: 3

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246548 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133446

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: 0.0000335

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.: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic homocystinuria Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 09, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 22, 2021	The homozygous c.752T>C (p.Leu251Pro) missense variant identified in the CBS gene has been reported in two affected individuals [PMID:24211323]. One individual [Patient #13] was homozygous for the p.Leu251Pro variant and presented with psychomotor delay and marfanoid features. The second individual [Patient #25] was compound heterozygous for p.Leu251Pro and another missense variant and presented with mild mental retardation, vision problems, and lens ectopia [PMID:24211323]. The p.Leu251Pro has been reported in ClinVar database as a variant of uncertain significance [Variation ID:555482]. The variant is absent from the gnomAD(v3) database suggesting it is not a common benign variant in populations represented in that database. The variant affects a moderately conserved residue and is predicted deleterious by multiple in silico tools [REVEL score= 0.99, CADD score= 32). Functional studies to evaluate the potential consequences of this variant have not been reported. Based on the available evidence, the homozygous c.752T>C (p.Leu251Pro)missense variant identified in the CBS gene is reported as a variant of uncertain significance. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 16, 2024

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 251 of the CBS protein (p.Leu251Pro). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with homocystinuria due to cystathionine beta-synthase deficiency (PMID: 24211323). ClinVar contains an entry for this variant (Variation ID: 555482). 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%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

CBS-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The CBS c.752T>C variant is predicted to result in the amino acid substitution p.Leu251Pro. This variant has been reported in the homozygous or compound heterozygous state in two Turkish individuals with a neurological presentation and elevated homocysteine and methionine in plasma (Karaca et al. 2014. PubMed ID: 24211323). It was also reported in the homozygous state in a patient with classical homocystinuria (Wasim et al. 2022. PubMed ID: 34905667). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. Taken together, this variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	.;.;.;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.3	M;M;M;M
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-4.7	D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90
MutPred		0.85		Loss of stability (P = 0.0052);Loss of stability (P = 0.0052);Loss of stability (P = 0.0052);Loss of stability (P = 0.0052);
MVP		0.94
MPC		1.4
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.99
gMVP		0.99

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: rs1176770868; hg19: chr21-44484086;