ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1094G>A (p.Cys365Tyr) (rs119455954)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Miraca Genetics Laboratories, RCV000002761 SCV000807625 pathogenic Ceroid lipofuscinosis neuronal 2 2017-09-01 criteria provided, single submitter clinical testing This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: with W366X in a 7-year-old male with developmental delay/regression, hypertonia/spasticity, seizure, ataxia, myoclonus, progressive brain atrophy, vision loss; with c.509-1G>C in a 5-year-old male with developmental regression, truncal ataxia, seizure disorder, optic atrophy, diffuse brain atrophy. Heterozygotes are expected to be asymptomatic carriers.
Counsyl RCV000002761 SCV000220456 likely pathogenic Ceroid lipofuscinosis neuronal 2 2014-06-26 criteria provided, single submitter literature only
GeneDx RCV000189781 SCV000243429 likely pathogenic not provided 2018-12-28 criteria provided, single submitter clinical testing p.Cys365Tyr (TGT>TAT): c.1094 G>A in exon 9 of the TPP1 gene (NM_000391.3)The C365Y missense change has been reported previously as a homozygous and compound heterozygous mutation in individuals with late-infantile neuronal ceroid lipofuscinosis (Sleat et al., 1997; Sleat et al., 1999). The amino acid substitution is conservative as both Cystine and Tyrosine are uncharged, non-polar amino acid residues; however, the loss of a Cysteine may affect disulfide bond formation in the TPP1 protein. In addition, another missense mutation at this same position (C365R) has been reported previously in association with LINCL (Sleat et. al, 1997).
Integrated Genetics/Laboratory Corporation of America RCV000526403 SCV000696662 pathogenic Neuronal ceroid lipofuscinosis 2016-12-30 criteria provided, single submitter clinical testing Variant summary: The TPP1 c.1094G>A (p.Cys365Tyr) variant located in the Peptidase S8/S53 domain (via InterPro) causes a missense change involving the alteration of a Cysteine, which has been implicated to play a key role in disulfide linkages needed to stabilize the fold (Guhaniyogi_2009 (PMID: 19038967). In addition, 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121330 (1/60665), which does not exceed the estimated maximal expected allele frequency for a pathogenic TPP1 variant of 1/338. Multiple publications cite individuals affected with Late-Infantile Neuronal Ceroid-Lipofuscinoses, who are homozygous or compound heterozygous for the variant of interest. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "likely pathogenic" or "pathogenic." Therefore, the variant of interest has been classified as "Pathogenic."
Invitae RCV000526403 SCV000628893 pathogenic Neuronal ceroid lipofuscinosis 2018-08-11 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 365 of the TPP1 protein (p.Cys365Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is present in population databases (rs119455954, ExAC 0.003%). This variant has been reported in individuals affected with late infantile neuronal ceroid lipofuscinosis (PMID:  10330339, 9788728, 26075876). ClinVar contains an entry for this variant (Variation ID: 2642). This variant is also known as c.4655G>A and c.1107T>C in the literature. Experimental studies have shown that this missense change is associated with reduced TPP1 enzyme activity (PMID: 10330339). A different missense substitution at this codon (p.Cys365Arg) has been reported in individuals with late infantile neuronal ceroid lipofuscinosis (PMID:10330339, 9788728). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002761 SCV000022919 pathogenic Ceroid lipofuscinosis neuronal 2 1997-09-19 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000002761 SCV000091183 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided not provided

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