rs121964962

chr21-43062988-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM5 PP3_Strong PP5_Very_Strong

The NM_000071.3(CBS):c.919G>A(p.Gly307Ser) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G307A) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CBS NM_000071.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17 O: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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000071.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-43062987-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2777031.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 21-43062988-C-T is Pathogenic according to our data. Variant chr21-43062988-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-43062988-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CBS	NM_000071.3	c.919G>A	p.Gly307Ser	missense_variant	10/17	ENST00000398165.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CBS	ENST00000398165.8	c.919G>A	p.Gly307Ser	missense_variant	10/17	1	NM_000071.3	P1

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD3 exomes AF: 0.000155 AC: 39 AN: 251400 Hom.: 0 AF XY: 0.000169 AC XY: 23 AN XY: 135886

Gnomad AFR exome AF: 0.000123

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: 0.0000463

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.000326

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 46 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 26

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 0

Alfa AF: 0.000287 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000654

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Classic homocystinuria Pathogenic:8 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 08, 2019	The p.Gly307Ser variant in CBS has been reported in at least 11 homozygous, 4 compound heterozygous and 15 heterozygous (where the second variant has not been reported) probands with homocystinuria and segregated with disease in 5 affected family members (Hu 1993, Dawson 1996, Stabler 2013, Gallagher 1995, Moat 2004). It was also reported in 1 heterozygous individual with homocystinuria and reversible cerebral white matter abnormalities who was also heterozygous for the MTHFR c.677C>T variant (Ismayilova 2019). This variant has been reported in ClinVar (ClinVar ID 117). In addition, in vitro functional studies provide evidence that the variant leads to impaired protein function (Hu 1993, Hnizda 2012, Kozich 2010, Mayfield 2012). This variant has also been identified in 41/129158 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). However, this frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive homocystinuria. ACMG/AMP Criteria applied: PM3_very_strong, PP1_strong, PS3_supporting. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Nov 05, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CBS c.919G>A (p.Gly307Ser) variant is well described as a common pathogenic allele in individuals with homocystinuria of Celtic origin, accounting for 71% of disease associated alleles in Ireland, 21% in the UK and 8% in the US (Moat et al. 2004). The presence of a single allele almost always predicts non-responsiveness to pyroxidine therapy. The p.Gly307Ser variant has been reported in at least six studies in which it is found in a total of 44 individuals including 14 in a homozygous state (including two pairs of siblings), ten in a compound heterozygous state (four of whom were related), and 20 heterozygotes in whom a second allele has not yet been identified (Hu et al. 1993; Gallagher et al. 1995; Kim et al. 1997; Kelly et al. 2003; Moat et al. 2004; Stabler et al. 2013). The variant was also found in at least three unaffected heterozygous relatives. The variant was absent from 82 control chromosomes but is reported at a frequency of 0.00026 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies have demonstrated that the Gly307 residue is located in the catalytic site of the protein and results in the production of correctly assembled tetramers that are slightly unfolded with a shift towards unfolded intermediates. The catalytic activity of the p.Gly307Ser variant protein is completely abolished (Hu et al. 1993; Hnizda et al. 2012). Based on the collective evidence, the p.Gly307Ser variant is classified as pathogenic for homocystinuria. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000071.2(CBS):c.919G>A(G307S) is classified as pathogenic in the context of CBS-related homocystinuria, and is associated with the B6-non-responsive form of this disease. Sources cited for classification include the following: PMID 9889017, 20506325, 7506602 and 22267502. Classification of NM_000071.2(CBS):c.919G>A(G307S) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 04, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Child Health and Human Development Program, Research Institute of the McGill University Health Center	-	The c.919G>A (G307S) was identified in a patient of African & French Canadian origin in compound heterozygote with c.941G>C (V314A). Clinical characteristics included lens dislocation and elevated fasting homocysteine. Patient had a mild intellectual impairment and does not respond to treatment with vitamin B6. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	CBS: PM3:Very Strong, PM2, PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2019	Common pathogenic variant found on approximately 70% of alleles in patients of Celtic origin with homocystinuria due to cystathionine beta-synthase (CBS) deficiency and is usually associated with a more severe non-B6 responsive phenotype (Urreizti et al., 2006); Functional studies found that G307S is associated with significantly decreased CBS enzyme activity compared to wild-type (Hu et al. 1993; Kozich et al. 2010; Hnizda et al. 2012); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 7581402, 14722927, 7564249, 17319270, 12552044, 8744616, 22267502, 23733603, 22069143, 7506602, 16479318, 30609409, 30187370, 12686134, 18280597, 12124992, 9361025, 25636110, 20506325) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2014	- -

HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 28, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 307 of the CBS protein (p.Gly307Ser). This variant is present in population databases (rs121964962, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 7506602, 7581402, 8744616, 9889017, 23733603). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 117). 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%. Experimental studies have shown that this missense change affects CBS function (PMID: 20506325, 22267502). For these reasons, this variant has been classified as Pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2023

The p.G307S pathogenic mutation (also known as c.919G>A), located in coding exon 8 of the CBS gene, results from a G to A substitution at nucleotide position 919. The glycine at codon 307 is replaced by serine, an amino acid with similar properties. This alteration was described to account for about 70% of disease alleles in Ireland (Gallagher PM et al. Hum. Mutat., 1995;6:177-80), 21% in UK and 8% in US (Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). This alteration has been reported in the homozygous state in multiple individuals with homocysteinuria, as well as in the heterozygous state in patients with an (un)identified second allele (Dawson PA et al. Aust N Z J Med, 1996 Apr;26:180-5; Gallagher PM et al. Hum. Mutat., 1995;6:177-80; Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Moat SJ et al. Hum. Mutat., 2004 Feb;23:206). In addition, this alteration was reported to occur in the enzyme active site (Meier M et al. Biochim. Biophys. Acta, 2003 Apr;1647:206-13), and in vitro studies have consistently suggested that this change would abolish enzyme activity, probably by interfering with protein folding (Kim CE et al. Hum. Mol. Genet., 1997 Dec;6:2213-21; Kozich V et al. Hum. Mutat., 2010 Jul;31:809-19; Mayfield JA et al. Genetics, 2012 Apr;190:1309-23; Hnízda A et al. J. Inherit. Metab. Dis., 2012 May;35:469-77). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Homocystinuria, pyridoxine-nonresponsive Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 28, 2003

- -

Homocystinuria Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Apr 06, 2017

Variant summary: The CBS c.919G>A (p.Gly307Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 19/121292 control chromosomes at a frequency of 0.0001566, which does not exceed the estimated maximal expected allele frequency of a pathogenic CBS variant (0.0030414). This variant has been reported in many affected individuals and functional study showed variant with <1% activity in comparison with WT (Kozich_2010). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

CBS-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 18, 2024

The CBS c.919G>A variant is predicted to result in the amino acid substitution p.Gly307Ser. This variant is one of the most commonly reported CBS variants causative for homocystinuria due to cystathionine beta-synthase deficiency (e.g., Gallagher et al. 1995. PubMed ID: 7581402; Kraus et al. 1999. PubMed ID: 10338090). In experimental studies, the p.Gly307Ser substitution has been shown to greatly impair CBS enzyme activity (Kozich et al. 2010. PubMed ID: 20506325; Mayfield et al. 2012. PubMed ID: 22267502). This variant is reported in 0.032% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;D;D;D
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M;M;M
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.6	D;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MVP		0.95
MPC		1.1
ClinPred		0.73	D
GERP RS		4.7
Varity_R		0.95
gMVP		0.97

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: rs121964962; hg19: chr21-44483098; COSMIC: COSV61446378; COSMIC: COSV61446378;