21-43062311-C-T

Variant names:

• chr21-43062311-C-T
• rs771298943
• NM_000071.3:c.1039G>A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_Moderate PP5_Very_Strong

The NM_000071.3(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 (★★).

• Frequency: Genomes: not found (cov: 0)
• Consequence: CBS NM_000071.3 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 10 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• 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 rank	MANE	Protein	UniProt
CBS	NM_000071.3	c.1039G>A	p.Gly347Ser	missense_variant, splice_region_variant	Exon 11 of 17	ENST00000398165.8	NP_000062.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBS	ENST00000398165.8	c.1039G>A	p.Gly347Ser	missense_variant, splice_region_variant	Exon 11 of 17	1	NM_000071.3	ENSP00000381231.4

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

May 22, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Child Health and Human Development Program, Research Institute of the McGill University Health Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Mar 21, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

May 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 05, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_supporting, PM3, PS3, PS4_moderate -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Dec 14, 2018

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;