ClinVar Miner

Submissions for variant NM_000049.2(ASPA):c.770C>G (p.Pro257Arg) (rs377217076)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668788 SCV000793444 uncertain significance Spongy degeneration of central nervous system 2017-08-16 criteria provided, single submitter clinical testing
GeneDx RCV000494038 SCV000582889 likely pathogenic not provided 2016-09-22 criteria provided, single submitter clinical testing The P257R variant in the ASPA gene has not been reported previously in a peer reviewed journal as a pathogenic variant, nor as a benign variant, to our knowledge. However, in an abstract by Kurczynski, TW and Victoria, MC (2011), the P257R and A305E variants were identified in an individual with atypical Canavan disease. Functional studies demonstrate that the P257R variant confers 21% enzyme activity as compared to wild-type and has reduced thermal stability (Zano et al., 2013). The P257R variant was not observed at a significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P257R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. The P257R variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

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