Submissions for variant NM_000310.3(PPT1):c.2T>C (p.Met1Thr) (rs796052927)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188725	SCV000242349	pathogenic	not provided	2013-04-25	criteria provided, single submitter	clinical testing	p.Met1Thr (ATG>ACG): c.2 T>C in exon 1 of the PPT1 gene (NM_000310.3). The c.2 T>C mutation alters the initiator Methionine codon, and the resultant protein would be best described as ?p.Met1?? to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine initiator codon. Although the c.2 T>C mutation in the PPT1 gene has not been previously published as a mutation to our knowledge, it is predicted to alter the normal protein and is therefore considered a disease-causing mutation. Moreover, another mutation that also affects the Methionine initiator codon, c.3 G>A, has been published in association with neuronal ceroid lipofuscinosis (Das et al., 1998). The variant is found in EPILEPSY panel(s).
Counsyl	RCV000410251	SCV000486588	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2016-06-29	criteria provided, single submitter	clinical testing
Invitae	RCV000410251	SCV001405566	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2019-07-27	criteria provided, single submitter	clinical testing	This sequence change affects the initiator methionine of the PPT1 mRNA. The next in-frame methionine is located at codon 41. This variant is not present in population databases (ExAC no frequency). Disruption of this initiator methionine has been observed in combination with another PPT1 variant in several individuals affected with neuronal ceroid lipofuscinosis (PMID: 9664077, 11073228, 11440996). ClinVar contains an entry for this variant (Variation ID: 206651). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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