Submissions for variant NM_000071.3(CBS):c.146C>T (p.Pro49Leu)

gnomAD frequency: 0.00013  dbSNP: rs148865119

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200523	SCV000249719	pathogenic	not provided	2023-03-14	criteria provided, single submitter	clinical testing	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: 29352562, 23974653, 10338090, 28550590, 22612060, 9587029, 25087612, 20506325, 28421128, 20308073, 25331909, 22985361, 31589614, 32768567, 33848968, 21520339, 12124992, 25218699, 18280597, 23733603)
Ambry Genetics	RCV002310761	SCV000317366	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-03-27	criteria provided, single submitter	clinical testing	The p.P49L pathogenic mutation (also known as c.146C>T), located in coding exon 1 of the CBS gene, results from a C to T substitution at nucleotide position 146. The proline at codon 49 is replaced by leucine, an amino acid with similar properties. This mutation was detected in a patient with homocystinuria, who also had an in-frame deletion and was pyridoxine responsive (De Franchis R, et al. Eur J Pediatr. 1998;157:S67-70). In addition this alteration was observed in conjunction with a splice site mutation in a patient who presented with deep vein thrombosis along with cardiac, ocular, and skeletal symptoms; however, information on phase was not provided (Evangelisti L, Int. J. Cardiol. 2009 May; 134(2):251-4). This alteration has been reported in an individual with a history of severe thoracic aortic aneurysm, but who also harbored an ACTA2 variant (Landis BJ et al. J Cardiovasc Transl Res, 2017 May). In another study, this mutation was detected in a mildly affected patient and his asymptomatic sister, both of whom carried a mild mutation in the other CBS allele. Functional studies showed that p.P49L was associated with mildly reduced enzyme activity (about 75% of the wild type) (Cozar M, et al. Hum Mutat. 2011;32(7):835-842). A further study determined that protein expression in fibroblasts from a homozygous individual were decreased. In addition, both protein levels and enzymatic activity were reduced to approximately 40% when expressed in vitro. However, the protein maintained normal response levels to its activator protein (Mendes J. Inherit. Metab Dis. 2014;37(2):25-254). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV002229028	SCV000543521	pathogenic	HYPERHOMOCYSTEINEMIA, THROMBOTIC, CBS-RELATED	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 49 of the CBS protein (p.Pro49Leu). This variant is present in population databases (rs148865119, gnomAD 0.03%). This missense change has been observed in individual(s) with homocystinuria (PMID: 9587029, 12124992, 18280597, 21520339, 23733603, 23974653, 25218699, 29352562). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 212872). 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: 21520339, 22985361, 23974653). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000410155	SCV000893557	pathogenic	Classic homocystinuria	2018-10-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000200523	SCV001472722	likely pathogenic	not provided	2020-01-09	criteria provided, single submitter	clinical testing	The CBS c.146C>T; p.Pro49Leu variant (rs148865119) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with homocystinuria, but is associated with a mild clinical phenotype (Cozar 2011, De Franchis 1998, Gaustadnes 2002, Mendes 2014, Stabler 2013). This variant is reported in ClinVar (Variation ID: 212872), and is found in the general population with an overall allele frequency of 0.015% (42/281978 alleles) in the Genome Aggregation Database. The proline at codon 49 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate a mild decrease in protein expression and function (Cozar 2011, Mendes 2014, Pey 2013, Vicente 2017). Based on available information, this variant is considered to be likely pathogenic. References: Cozar M et al. Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients. Hum Mutat. 2011 Jul;32(7):835-42. De Franchis R et al. Clinical aspects of cystathionine beta-synthase deficiency: how wide is the spectrum? The Italian Collaborative Study Group on Homocystinuria. Eur J Pediatr. 1998 Apr;157 Suppl 2:S67-70. Gaustadnes M et al. The molecular basis of cystathionine beta-synthase deficiency in Australian patients: genotype-phenotype correlations and response to treatment. Hum Mutat. 2002 Aug;20(2):117-26. Mendes MI et al. Reduced response of Cystathionine Beta-Synthase (CBS) to S-Adenosylmethionine (SAM): Identification and functional analysis of CBS gene mutations in Homocystinuria patients. J Inherit Metab Dis. 2014 Mar;37(2):245-54. Pey AL et al. Human cystathionine ß-synthase (CBS) contains two classes of binding sites for S-adenosylmethionine (SAM): complex regulation of CBS activity and stability by SAM. Biochem J. 2013 Jan 1;449(1):109-21. Stabler SP et al. Metabolic profiling of total homocysteine and related compounds in hyperhomocysteinemia: utility and limitations in diagnosing the cause of puzzling thrombophilia in a family. JIMD Rep. 2013;11:149-63. Vicente JB et al. A Clinically Relevant Variant of the Human Hydrogen Sulfide-Synthesizing Enzyme Cystathionine ß-Synthase: Increased CO Reactivity as a Novel Molecular Mechanism of Pathogenicity? Oxid Med Cell Longev. 2017;2017:8940321.
Mayo Clinic Laboratories, Mayo Clinic	RCV000200523	SCV001713879	likely pathogenic	not provided	2020-12-07	criteria provided, single submitter	clinical testing	PS3, PM3, PP3
Revvity Omics, Revvity	RCV000410155	SCV002016939	pathogenic	Classic homocystinuria	2022-03-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410155	SCV004213842	pathogenic	Classic homocystinuria	2024-03-20	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000410155	SCV004847929	likely pathogenic	Classic homocystinuria	2019-03-20	criteria provided, single submitter	clinical testing	The p.Pro49Leu variant in CBS has been reported in 7 compound heterozygous and 1 homozygous individuals with mild homocystinuria, and segregated with disease in 1 affected relative (Alcaide 2015, Cozar 2011, Evangelisti 2009, Gaustadnes 2002, Mendes 2014, Poloni 2018). In addition, it segregated with thromboembolic episodes in one family without the associated ocular, skeletal, or CNS abnormalities (Stabler 2013). It was also found in an asymptomatic sibling with hyperhomocysteinemia and hypermethioninemia but had no clinical sign of classical homocystinuria and had given birth to three healthy offspring without complications (Cozar 2011). It has also been identified in 0.031% (40/128366) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 212872). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In vitro and in vivo functional studies support a mild impact on protein function (Alcaide 2015, Cozar 2011, Hnizda 2012, Kozich 2010, Mendes 2014, Vicente 2017). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for mild homocystinuria. ACMG/AMP Criteria applied: PM3_Very Strong, PP1, PS3_Supporting.
CeGaT Center for Human Genetics Tuebingen	RCV000200523	SCV005051295	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	CBS: PM3:Strong, PM2, PS3:Supporting
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000410155	SCV005052058	pathogenic	Classic homocystinuria	2024-02-01	criteria provided, single submitter	curation
Counsyl	RCV000410155	SCV000486645	likely pathogenic	Classic homocystinuria	2016-07-21	no assertion criteria provided	clinical testing