Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000049590 | SCV000220645 | likely pathogenic | Neuronal ceroid lipofuscinosis 1 | 2014-08-28 | criteria provided, single submitter | literature only | |
| Invitae | RCV000049590 | SCV003523270 | uncertain significance | Neuronal ceroid lipofuscinosis 1 | 2022-09-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 42 of the PPT1 protein (p.Gly42Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 9664077). ClinVar contains an entry for this variant (Variation ID: 56179). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PPT1 function (PMID: 11440996). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317067 | SCV004020550 | likely pathogenic | Neuronal ceroid lipofuscinosis | 2023-06-13 | criteria provided, single submitter | clinical testing | Variant summary: PPT1 c.125G>A (p.Gly42Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a canonical 3' acceptor site and two predict the variant weakens the 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251424 control chromosomes (gnomAD). c.125G>A has been reported in the literature as a compound heterozygous genotype in two siblings affected with infantile onset Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Das_1998, Hofmann_1999). These data indicate that the variant may be associated with disease. Additionally, a functional study found the variant showed no detectable instrinsic enzyme activity in vitro, with <2% activity of the WT protein (Das_2001). The following publications have been ascertained in the context of this evaluation (PMID: 11440996, 9664077, 10191107). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000049590 | SCV004204148 | likely pathogenic | Neuronal ceroid lipofuscinosis 1 | 2023-07-26 | criteria provided, single submitter | clinical testing | |
| Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000049590 | SCV000081997 | probable-pathogenic | Neuronal ceroid lipofuscinosis 1 | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. |