chr21-43062311-C-T

Position:

• chr21-43062311-C-T

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.1039G>A​(p.Gly347Ser) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G347A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS ENST00000398165.8 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• 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 Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000398165.8
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 21-43062311-C-T is Pathogenic according to our data. Variant chr21-43062311-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062311-C-T is described in Lovd as [Pathogenic]. Variant chr21-43062311-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CBS	NM_000071.3	c.1039G>A	p.Gly347Ser	missense_variant, splice_region_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.1039G>A	p.Gly347Ser	missense_variant, splice_region_variant	11/17	1	NM_000071.3	ENSP00000381231	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Child Health and Human Development Program, Research Institute of the McGill University Health Center	-	The c.1039G>A (G347S) was identified in a patients of Eastern European origin in compound heterozygote with c.526G>A (E176K). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patients had no intellectual impairment and do not respond to treatment with vitamin B6. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 21, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate that p.(G347S) is associated with very low levels of residual cystathionine beta-synthase enzyme activity compared to wild-type (PMID: 12124992); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22267502, 16205833, 21517828, 24211323, 19914636, 16307898, 19370759, 30202406, 12124992) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 05, 2023	PP3, PM2_supporting, PM3, PS3, PS4_moderate -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 22, 2024

The p.G347S pathogenic mutation (also known as c.1039G>A), located in coding exon 9 of the CBS gene, results from a G to A substitution at nucleotide position 1039. The glycine at codon 347 is replaced by serine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 9 and may have some effect on normal mRNA splicing. This variant has been identified in the homozygous state and/or in conjunction with other CBS variant(s) in individual(s) with features consistent with homocystinuria (Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Lee SJ et al. J. Hum. Genet., 2005 Oct;50:648-54; Katsushima F et al. Mol. Genet. Metab., 2006 Apr;87:323-8; Zschocke J et al. Hum. Mutat., 2009 Jun;30:1021-2; Karaca M et al. Gene, 2014 Jan;534:197-203; Yubero D et al. PLoS ONE, 2016 May;11:e0156359; Alfares AA. Int J Health Sci (Qassim). 2018;12:35-43). In addition, this variant has been reported to result in absence of, or significantly reduced, enzyme activity in various expression systems, and was reported as non-functional in a yeast growth assay (Gaustadnes M et al. Hum. Mutat., 2002 Aug;20:117-26; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Lee SJ et al. J. Hum. Genet., 2005 Oct;50:648-54). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice donor site. This amino acid position is highly conserved in available vertebrate species. In addition, as a missense substitution, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 05, 2024

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 347 of the CBS protein (p.Gly347Ser). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs771298943, gnomAD 0.007%). This missense change has been observed in individuals with homocystinuria (PMID: 12124992, 16205833, 16307898, 19370759, 24211323). ClinVar contains an entry for this variant (Variation ID: 188801). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CBS function (PMID: 22267502). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 14, 2018

Variant summary: CBS c.1039G>A (p.Gly347Ser) 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 3.2e-05 in 30882 control chromosomes. c.1039G>A has been reported in the literature in multiple individuals affected with Homocystinuria (Gaustadnes_2002, Lee_2005, Katsushima_2006, Karaca_2014, Yubero_2016). 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 <10% of normal activity (Lee_2005). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant 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	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	.;.;.;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.8	H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.86
MutPred		0.96		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.94
MPC		1.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs771298943; hg19: chr21-44482421; COSMIC: COSV61442621; COSMIC: COSV61442621;