ClinVar Miner

Submissions for variant NM_000071.2(CBS):c.146C>T (p.Pro49Leu) (rs148865119)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200523 SCV000249719 likely pathogenic not provided 2021-08-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as pathogenic or likely pathogenic (ClinVar Variant ID# 212872; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 21520339, 23974653, 28550590, 12124992, 25218699, 9587029, 18280597, 20506325, 23733603, 29352562, 32768567, 33848968, 31589614, 22985361, 25331909, 20308073, 28421128, 25087612, 10338090, 22612060)
Ambry Genetics RCV000242293 SCV000317366 pathogenic Cardiovascular phenotype 2020-09-01 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; [epub ahead of print]). 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 RCV000410155 SCV000543521 likely pathogenic Classic homocystinuria 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 49 of the CBS protein (p.Pro49Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs148865119, ExAC 0.03%). ClinVar contains an entry for this variant (Variation ID: 212872). This variant has been reported in individuals with homocystinuria (PMID: 9587029, 12124992, 21520339, 23733603, 23974653, 18280597, 25218699, 29352562) and was shown to segregate with intermittent homocystinuria in one family (PMID: 23733603). However, this variant did not segregate with homocystinuria in a second family (PMID: 21520339). ClinVar contains an entry for this variant (Variation ID: 212872). Experimental studies have shown that this missense change has a mild effect on protein expression and function (PMID: 21520339, 22985361, 23974653). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with homocystinuria (Invitae database). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. In summary, this variant has been found in affected individuals, occurring in trans with a second pathogenic CBS variant in one of them, and has been shown to have a mild effect on protein function. However, segregation studies are conflicting. In the absence of more definitive segregation evidence or functional data, at this time this change has been classified as Likely 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 RCV001286191 SCV001472722 likely pathogenic none 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
Counsyl RCV000410155 SCV000486645 likely pathogenic Classic homocystinuria 2016-07-21 no assertion criteria provided clinical testing

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