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
Ambry Genetics RCV000242293 SCV000317366 pathogenic Cardiovascular phenotype 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous
Counsyl RCV000410155 SCV000486645 likely pathogenic Homocystinuria due to CBS deficiency 2016-07-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000410155 SCV000893557 pathogenic Homocystinuria due to CBS deficiency 2018-10-31 criteria provided, single submitter clinical testing
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)."
Invitae RCV000410155 SCV000543521 likely pathogenic Homocystinuria due to CBS deficiency 2018-12-10 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.

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