Submissions for variant NM_000391.4(TPP1):c.1033A>C (p.Met345Leu)

gnomAD frequency: 0.00007  dbSNP: rs141482368

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000259663	SCV000373324	likely benign	Neuronal ceroid lipofuscinosis 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV000632726	SCV000514961	benign	not provided	2018-05-23	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30541466)
Invitae	RCV000632726	SCV000753912	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000259663	SCV001737173	likely benign	Neuronal ceroid lipofuscinosis 2	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222484	SCV002500200	likely benign	not specified	2022-03-08	criteria provided, single submitter	clinical testing	Variant summary: TPP1 c.1033A>C (p.Met345Leu) results in a conservative amino acid change located in the Peptidase S8/S53 domain (IPR000209) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 251448 control chromosomes, predominantly at a frequency of 0.013 within the South Asian subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in TPP1 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.1033A>C has been reported in the literature in a heterozygous individual (non-informative genotype) reportedly affected with Neuronal Ceroid-Lipofuscinosis without evidence for causality (Sheth_2018). This report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000632726	SCV002544538	benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	TPP1: BS1, BS2
Fulgent Genetics, Fulgent Genetics	RCV002502207	SCV002808905	likely benign	Neuronal ceroid lipofuscinosis 2; Autosomal recessive spinocerebellar ataxia 7	2022-04-08	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000259663	SCV001458786	benign	Neuronal ceroid lipofuscinosis 2	2020-01-10	no assertion criteria provided	clinical testing