Submissions for variant NM_000310.4(PPT1):c.433G>C (p.Gly145Arg)

gnomAD frequency: 0.00001  dbSNP: rs369186379

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178074	SCV000230066	uncertain significance	not provided	2014-11-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002317045	SCV000851125	uncertain significance	Inborn genetic diseases	2016-07-28	criteria provided, single submitter	clinical testing	The c.433G>C variant (also known as p.G145R), located in coding exon 4 of the PPT1 gene, results from a G to C substitution at nucleotide position 433. The amino acid change results in glycine to arginine at codon 145, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. Based on data from the NHLBI Exome Sequencing Project (ESP), the C allele has an overall frequency of approximately 0.01% (1/13006) total alleles studied, having been observed in 0.02% (1/4406) African American alleles. Both the nucleotide and amino acid positions are highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001420748	SCV001623091	uncertain significance	not specified	2021-04-22	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.433G>C (p.Gly145Arg) 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. The variant is located near a canonical splice site. Several computational tools predict an impact on normal splicing: 4 predict that the variant weakens or abolishes a 5-prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.433G>C in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and no experimental evidence demonstrating an impact on protein function have been reported. One other clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001826905	SCV003288281	uncertain significance	Neuronal ceroid lipofuscinosis 1	2022-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 145 of the PPT1 protein (p.Gly145Arg). This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PPT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 197131). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
GeneDx	RCV000178074	SCV005079119	likely pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	Occurs in the last nucleotide of an exon in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Identified in the single heterozygous state without a second PPT1 variant in an individual who had a different genetic etiology for the phenotype (PMID: 30378543); This variant is associated with the following publications: (PMID: 30378543)
Natera, Inc.	RCV001826905	SCV002085992	uncertain significance	Neuronal ceroid lipofuscinosis 1	2021-04-22	no assertion criteria provided	clinical testing