Submissions for variant NM_000310.3(PPT1):c.29T>A (p.Leu10Ter) (rs137852699)

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000009454	SCV000220758	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2014-09-30	criteria provided, single submitter	literature only
GeneDx	RCV000188716	SCV000242340	pathogenic	not provided	2018-11-21	criteria provided, single submitter	clinical testing	The L10X nonsense variant in the PPT1 gene has been reported previously in several families with infantile or juvenile neuronal ceroid lipofuscinosis (NCL) who had a second pathogenic variant on the opposite allele (Mitchison et al., 1998; Miller et al., 2013). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Functional analysis showed L10X is associated with decreased mRNA and enzyme activity levels (Das et al., 2001; Miller et al., 2013).
Invitae	RCV000009454	SCV000550823	pathogenic	Neuronal ceroid lipofuscinosis 1	2020-09-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu10*) in the PPT1 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs137852699, ExAC 0.01%). This variant has been observed in individuals affected with juvenile or infantile neuronal ceroid lipofuscinosis (PMID: 9425237, 23539563, 9664077). ClinVar contains an entry for this variant (Variation ID: 8903). Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000715556	SCV000846385	pathogenic	History of neurodevelopmental disorder	2016-05-12	criteria provided, single submitter	clinical testing	The p.L10* pathogenic mutation (also known as c.29T>A), located in coding exon 1 of the PPT1 gene, results from a T to A substitution at nucleotide position 29. This changes the amino acid from a leucine to a stop codon within coding exon 1. This mutation was reported in the homozygous state in an individual diagnosed with autosomal recessive infantile neuronal ceroid lipofuscinosis (INCL) (MunroePB et al., J. Med. Genet. 1998; 35(9):790). This mutation has also been found in multiple individuals who were compound heterozygotesfor p.L10* along with anothermutationin PPT1 and diagnosed with juvenile onset neuronal ceroid lipofuscinosis/granular osmiophilic deposits (JNCL/GROD) (MitchisonHM et al., Hum. Mol. Genet. 1998; 7(2):291-7). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000188716	SCV000854968	pathogenic	not provided	2017-09-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000009454	SCV000920081	pathogenic	Neuronal ceroid lipofuscinosis 1	2017-12-15	criteria provided, single submitter	clinical testing	Variant summary: The PPT1 c.29T>A (p.Leu10X) variant results in a premature termination codon, predicted to cause a truncated or absent PPT1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study determined less than 10% PPT activity in PBLs in a patient carrying this mutation (Mitchison_1998). One truncation downstream of this position has been classified as pathogenic by our laboratory (e.g. c.451C>T, p.Arg151X). One in silico tool predicts a damaging outcome for this variant. This variant was found in 20/276316 control chromosomes (gnomAD) at a frequency of 0.0000724, which does not exceed the estimated maximal expected allele frequency of a pathogenic PPT1 variant (0.0007331). This variant has been reported in multiple patients with NCL, in both homozygotes and heterozygotes (Das_1998, Mitchison_1998, Stephenson_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV000009454	SCV001162888	pathogenic	Neuronal ceroid lipofuscinosis 1		criteria provided, single submitter	clinical testing
OMIM	RCV000009454	SCV000029672	pathogenic	Neuronal ceroid lipofuscinosis 1	1998-02-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000009454	SCV001453967	pathogenic	Neuronal ceroid lipofuscinosis 1	2020-09-16	no assertion criteria provided	clinical testing