Submissions for variant NM_000310.4(PPT1):c.541G>A (p.Val181Met)

gnomAD frequency: 0.00006  dbSNP: rs148412181

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169209	SCV000220464	likely pathogenic	Neuronal ceroid lipofuscinosis 1	2014-06-27	criteria provided, single submitter	literature only
Invitae	RCV000169209	SCV000958226	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 181 of the PPT1 protein (p.Val181Met). This variant is present in population databases (rs148412181, gnomAD 0.02%). This missense change has been observed in individuals with neuronal ceroid lipofucinosis (NCL) (PMID: 9664077, 10191107, 10649502, 15464427, 19302939, 22387303, 23374165, 30541466). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188857). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PPT1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects PPT1 function (PMID: 9664077, 11440996, 28878621). This variant disrupts the p.Val181 amino acid residue in PPT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19302939, 21499717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000169209	SCV000965817	pathogenic	Neuronal ceroid lipofuscinosis 1	2016-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169209	SCV001361117	pathogenic	Neuronal ceroid lipofuscinosis 1	2019-03-11	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.541G>A (p.Val181Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 277014 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (8.7e-05 vs 0.00073), allowing no conclusion about variant significance. c.541G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease, Das_1998, Santorelli_2013, Poyato_2012). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein enzyme activity. The most pronounced variant effect results in <10% of normal activity (Das_1998, Poyato_2012). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000169209	SCV001571358	pathogenic	Neuronal ceroid lipofuscinosis 1	2021-04-12	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001723740	SCV001950330	pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Val181Met variant in PPT1 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM3, PS3, PP1-M, PM1. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
GeneDx	RCV002259317	SCV002538723	pathogenic	not provided	2022-06-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that V181M results in almost complete loss of wild-type function (Das et al., 2001); Located in the palmitate-binding site and it is hypothesized that the V181M substitution alters the active site pocket (Ohno et al., 2010); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15464427, 12796825, 12125808, 28878621, 11073228, 11589007, 21990111, 21499717, 24091420, 15965709, 10649502, 31589614, 30541466, 33726816, 23374165, 33849402, 22387303, 11440996, 19793631, 9664077)
Ambry Genetics	RCV002345567	SCV002649347	pathogenic	Inborn genetic diseases	2019-07-19	criteria provided, single submitter	clinical testing	The p.V181M pathogenic mutation (also known as c.541G>A), located in coding exon 6 of the PPT1 gene, results from a G to A substitution at nucleotide position 541. The valine at codon 181 is replaced by methionine, an amino acid with highly similar properties. This mutation has been identified in multiple individuals with neuronal ceroid lipofuscinosis, including in the homozygous state in 3 individuals from 2 families (Das AK et al. J. Clin. Invest., 1998 Jul;102:361-70; Waliany S et al. Hum. Mutat., 2000 Feb;15:206-7; Mole SE et al. Hum. Mutat., 1999;14:199-215; Teixeira C et al. J. Neurol., 2003 Jun;250:661-7; P&eacute;rez Poyato MS et al. Gene, 2012 May;499:297-302; Santorelli FM et al. Orphanet J Rare Dis, 2013 Feb;8:19; Sheth J et al. BMC Neurol, 2018 Dec;18:203). Analysis of this mutation in SF9 cells as well as patient derived lymphoblasts showed o detectable palmitoyl-protein thioesterase activity (Das AK et al. Hum. Mol. Genet., 2001 Jun;10:1431-9). Another study suggested abnormal processing of protein containing this mutation (Pezzini F et al. Front Mol Neurosci, 2017 Aug;10:266). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000169209	SCV003826627	pathogenic	Neuronal ceroid lipofuscinosis 1	2022-03-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169209	SCV004204132	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-03-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000169209	SCV002085986	pathogenic	Neuronal ceroid lipofuscinosis 1	2021-06-07	no assertion criteria provided	clinical testing