ClinVar Miner

Submissions for variant NM_000310.4(PPT1):c.29T>A (p.Leu10Ter)

gnomAD frequency: 0.00004  dbSNP: rs137852699
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Total submissions: 9
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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 2023-03-24 criteria provided, single submitter clinical testing Has been reported previously in several families with infantile or juvenile neuronal ceroid lipofuscinosis (NCL) in the compound heterozygous state with a second variant or in the homozygous state (Mitchison et al., 1998; Das et al., 1998; Miller et al., 2013); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Published functional studies demonstrate L10X associated with decreased mRNA and enzyme activity levels (Das et al., 2001; Miller et al., 2013).; This variant is associated with the following publications: (PMID: 21990111, 9733046, 11073228, 21704547, 15965709, 9425237, 31741823, 9664077, 23539563, 31440721, 34733232, 11440996)
Invitae RCV000009454 SCV000550823 pathogenic Neuronal ceroid lipofuscinosis 1 2024-01-23 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. Loss-of-function variants in PPT1 are known to be pathogenic (PMID: 10679943, 21990111). This variant is present in population databases (rs137852699, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with juvenile or infantile neuronal ceroid lipofuscinosis (PMID: 9425237, 9664077, 23539563). ClinVar contains an entry for this variant (Variation ID: 8903). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002311509 SCV000846385 pathogenic Inborn genetic diseases 2022-04-25 criteria provided, single submitter clinical testing The c.29T>A (p.L10*) alteration, located in exon 1 (coding exon 1) of the PPT1 gene, consists of a T to A substitution at nucleotide position 29. This changes the amino acid from a leucine (L) to a stop codon at amino acid position 10. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of 0.01% (21/281870) total alleles studied. The highest observed frequency was 0.02% (20/128290) of European (non-Finnish) alleles. This mutation was reported in the homozygous state in an individual diagnosed with autosomal recessive infantile neuronal ceroid lipofuscinosis (Munroe, 1998). This mutation has also been found in multiple individuals who were compound heterozygotes for p.L10* along with another mutation in PPT1 and diagnosed with juvenile onset neuronal ceroid lipofuscinosis/granular osmiophilic deposits (Mitchison, 1998). Based on the available evidence, this alteration is classified as pathogenic.
Eurofins Ntd Llc (ga) 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

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