Total submissions: 1
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189789 | SCV000243437 | uncertain significance | not provided | 2014-05-20 | criteria provided, single submitter | clinical testing | p.Ala444Asp (GCC>GAC): c.1331 C>A in exon 11 of the TPP1 gene (NM_000391.3) The A444D variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. However, the A444D 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, and missense mutations in nearby residues (R447H and A448V) have been reported in association with late infantileneuronal ceroid lipofuscinosis supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant and is interpreted to be of uncertain significance. The variant is found in INFANT-EPI panel(s). |