ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200523 SCV000249719 likely pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The P49L likely pathogenic variant in the CBS gene has been previously reported in patients clinically diagnosed with homocystinuria (de Franchis et al., 1998; Evangelisti et al., 2009; Kozich et al., 2010; Cozar et al., 2011). The P49L variant is responsive to pyridoxine (vitamin B6), which is associated with a milder clinical phenotype and slower disease progression (de Franchis et al., 1998; Alcaide et al., 2015). Stabler et al. (2013) identified P49L (in conjunction with the CBS G307S variant) in a family who presented with thrombotic disease in the absence of other homocystinuria-associated ocular, skeletal, or CNS anomalies. P49L was also identified incidentally via whole exome sequencing in a patient with a severe thoracic aortic aneurysm" phenotype; however, the affected individual also harbored a pathogenic ACTA2 gene variant, which was believed to fully explain phenotype (Landis et al., 2017). P49L is classified in ClinVar as either a pathogenic or likely pathogenic variant by three other clinical laboratories (SCV000317366.1, SCV000486645.1, SCV000543521.1; Landrum et al., 2016). The P49L variant is observed in 22/65,942 (0.03%) alleles from individuals of European (Non-Finnish) ancestry in the Exome Aggregation Consortium, but not present in the homozygous state (Lek et al., 2016). P49L is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Published functional studies indicate this variant leads to a moderate decrease in enzyme activity (Mendes et al., 2014; Cozar et al., 2011)."
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 2019-10-20 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
Counsyl RCV000410155 SCV000486645 likely pathogenic Classic homocystinuria 2016-07-21 no assertion criteria provided clinical testing

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