Submissions for variant NM_000310.4(PPT1):c.329A>G (p.Asn110Ser)

gnomAD frequency: 0.00010  dbSNP: rs142894102

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724058	SCV000228845	uncertain significance	not provided	2014-08-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000724058	SCV000242336	uncertain significance	not provided	2024-09-20	criteria provided, single submitter	clinical testing	Reported in the heterozygous state in a patient with cognitive impairment, ADHD, and epilepsy in the published literature; however, a second PPT1 variant was not identified (PMID: 33528079); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a homozygous state in a patient with episodic torticollis and sudden cardiac arrest who also harbored another homozygous variant in a gene related to the phenotype (PMID: 35693655); This variant is associated with the following publications: (PMID: 34426522, 35693655, 30541466, 33528079, Bhavsar2016[CaseReport])
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000625813	SCV000746371	uncertain significance	Neuronal ceroid lipofuscinosis 1	2017-12-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625813	SCV000818289	pathogenic	Neuronal ceroid lipofuscinosis 1	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 110 of the PPT1 protein (p.Asn110Ser). This variant is present in population databases (rs142894102, gnomAD 0.06%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 30541466). ClinVar contains an entry for this variant (Variation ID: 196249). 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 80%. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000625813	SCV002791947	uncertain significance	Neuronal ceroid lipofuscinosis 1	2022-04-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002516724	SCV003748459	uncertain significance	Inborn genetic diseases	2021-07-08	criteria provided, single submitter	clinical testing	The c.329A>G (p.N110S) alteration is located in exon 3 (coding exon 3) of the PPT1 gene. This alteration results from a A to G substitution at nucleotide position 329, causing the asparagine (N) at amino acid position 110 to be replaced by a serine (S). The in silico prediction for the p.N110S alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000625813	SCV003809831	uncertain significance	Neuronal ceroid lipofuscinosis 1	2021-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235097	SCV003934442	uncertain significance	not specified	2023-12-26	criteria provided, single submitter	clinical testing	Variant summary: PPT1 c.329A>G (p.Asn110Ser) 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 0.00019 in 251452 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in PPT1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00019 vs 0.0014), allowing no conclusion about variant significance. c.329A>G has been reported in the literature in the homozygous state in an individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) who had significantly reduced PPT1 enzyme activity compared to normal controls (Sheth_2018). These data indicate that the variant may be associated with disease. However, it has also been reported in the homozygous state in an individual from a consanguineous family, affected with Childhood Onset Neurodegeneration with Ataxia and Seizures, who had a normal PPT1 level and was also homozygous for a variant in the ADPRHL2 gene (c.235A>C, p.T79P) which may explain the phenotype (Ozturk_2022). Finally, the variant has also been reported as a heterozygous genotype in an individual affected with cognitive impairment, ADHD, and epilepsy (Atli_2022). Thus, these reports do not allow for any strong conclusions to be made about variant significance. The following publications have been ascertained in the context of this evaluation (PMID: 33528079, 30541466, 35693655). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=7) or pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000625813	SCV005400773	likely pathogenic	Neuronal ceroid lipofuscinosis 1		criteria provided, single submitter	clinical testing	The observed missense c.329A>G (p.Asn110Ser) variant in PPT1 gene has been reported previously in multiple individuals affected with PPT1-related disorders (Sheth et al., 2018; Atli et al., 2022; Ozturk et al., 2022). The p.Asn110Ser variant is present with allele frequency of 0.02% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic/ Uncertain Significance (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Asn110Ser in PPT1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 110 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252359	SCV001428113	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000625813	SCV001464023	uncertain significance	Neuronal ceroid lipofuscinosis 1	2020-09-16	no assertion criteria provided	clinical testing