rs781567152

Positions:

• chr21-43062391-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PP3_Strong PP5_Very_Strong

The ENST00000398165.8(CBS):​c.959T>C​(p.Val320Ala) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 14 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, 5 uncertain in ENST00000398165.8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 21-43062391-A-G is Pathogenic according to our data. Variant chr21-43062391-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062391-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.959T>C	p.Val320Ala	missense_variant	11/17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.959T>C	p.Val320Ala	missense_variant	11/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250352 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135590

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 10, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 24, 2023	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 01, 2018

The CBS c.959T>C; p.Val320Ala variant (rs781567152) is reported in the literature in multiple individuals affected with homocystinuria in both the homozygous state and in individuals with a second pathogenic variant (Kim 1997, Kruger 2003). This variant is reported in ClinVar (Variation ID: 371028), and it is found on only four chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant at this codon (p.Val320Gly) has been reported in an individual with homocystinuria and is considered pathogenic (Lu 2012). The valine at codon 320 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that the p.Val320Ala variant is deleterious. Consistent with these predictions, functional analyses demonstrate that the p.Val320Ala variant exhibits significantly lower enzymatic activity than wildtype protein (Kruger 2003, Singh 2010) and fails to rescue yeast growth on media lacking a source of cysteine (Kim 1997, Mayfield 2012). Based on available information, this variant is considered to be pathogenic. References: Kim CE et al. Functional modeling of vitamin responsiveness in yeast: a common pyridoxine-responsive cystathionine beta-synthase mutation in homocystinuria. Hum Mol Genet. 1997 Dec;6(13):2213-21. Kruger WD et al. Cystathionine beta-synthase deficiency in Georgia (USA): correlation of clinical and biochemical phenotype with genotype. Hum Mutat. 2003 Dec;22(6):434-41. Lu YH et al. Homocystinuria in Taiwan: an inordinately high prevalence in an Austronesian aboriginal tribe, Tao. Mol Genet Metab. 2012 Apr;105(4):590-5. Mayfield JA et al. Surrogate genetics and metabolic profiling for characterization of human disease alleles. Genetics. 2012 Apr;190(4):1309-23. Singh LR et al. Activation of mutant enzyme function in vivo by proteasome inhibitors and treatments that induce Hsp70. PLoS Genet. 2010 Jan;6(1):e1000807. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 23, 2023

This missense change has been observed in individual(s) with CBS-related conditions (PMID: 9361025, 14635102). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CBS function (PMID: 9361025, 14635102). 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. ClinVar contains an entry for this variant (Variation ID: 371028). This variant is present in population databases (rs781567152, gnomAD 0.004%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 320 of the CBS protein (p.Val320Ala). -

Homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 27, 2021

Variant summary: CBS c.959T>C (p.Val320Ala) 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 1.6e-05 in 245462 control chromosomes (gnomAD and publication). c.959T>C has been reported in the literature in individuals affected with Homocystinuria (Guttormsen_2001, Kruger_2003). These data indicate that the variant is likely to be associated with disease. Multiple publications have assessed the variant for functional implications, which showed that the most pronounced variant effect results in <10% of normal activity (Kim_1997, Kruger_2003, Singh_2010, Mayfield_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/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	Benign	0.34
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	.;.;.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D
Polyphen		0.98	D;D;D;D
Vest4		0.83
MutPred		0.86		Gain of disorder (P = 0.1046);Gain of disorder (P = 0.1046);Gain of disorder (P = 0.1046);Gain of disorder (P = 0.1046);
MVP		0.90
MPC		1.2
ClinPred		0.84	D
GERP RS		5.0
Varity_R		0.84
gMVP		0.94

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: rs781567152; hg19: chr21-44482501;