Submissions for variant NM_000310.4(PPT1):c.398del (p.Met133fs)

dbSNP: rs386833644

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049603	SCV000486363	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2016-05-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797615	SCV002041536	pathogenic	Neuronal ceroid lipofuscinosis	2021-11-24	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.398delT (p.Met133ArgfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251274 control chromosomes (gnomAD). c.398delT has been reported in the literature in 3 compound heterozygous siblings affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant is likely to be associated with disease. Experimental evidence derived from analysis of postmortem brain tissue from one compound heterozygous patient, demonstrated presence of numerous apoptotic cells and abnormally low levels of soluble synaptic vesicle proteins (Kim_2006, 2008). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Centogene AG - the Rare Disease Company	RCV000049603	SCV002059838	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2021-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV000049603	SCV003258814	pathogenic	Neuronal ceroid lipofuscinosis 1	2023-09-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Met133Argfs*4) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs386833644, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56192). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000049603	SCV004204144	pathogenic	Neuronal ceroid lipofuscinosis 1	2023-08-23	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049603	SCV000082010	probable-pathogenic	Neuronal ceroid lipofuscinosis 1		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.