ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.225A>G (p.Gln75=)

gnomAD frequency: 0.00004  dbSNP: rs368709098
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668623 SCV000793256 uncertain significance Neuronal ceroid lipofuscinosis 2 2017-08-08 criteria provided, single submitter clinical testing
Invitae RCV001215564 SCV001387315 pathogenic not provided 2023-12-22 criteria provided, single submitter clinical testing This sequence change affects codon 75 of the TPP1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TPP1 protein. This variant is present in population databases (rs368709098, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 10330339, 23418007, 34126256). This variant is also known as 1946A>G. ClinVar contains an entry for this variant (Variation ID: 553222). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris RCV001644760 SCV001519242 likely pathogenic Autosomal recessive spinocerebellar ataxia 7 2021-07-12 criteria provided, single submitter research
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000668623 SCV002768068 pathogenic Neuronal ceroid lipofuscinosis 2 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neuronal ceroid lipofuscinosis, 2 (MIM#204500), and spinocerebellar ataxia, autosomal recessive 7 (MIM#609270). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been functionally proven by RNA studies to cause the partial skipping of exon 3, resulting in a frameshift and the formation of a premature termination codon (p.(Tyr76Lysfs*10)). This transcript is predicted to undergo nonsense-mediated decay (NMD). There is some residual wildtype transcript, but this is at very low levels (<10%) (PMID: 34126256). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (8 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic and observed in individuals with neuronal ceroid lipofuscinosis (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS, but more recently as likely pathogenic and pathogenic, in multiple compound heterozygous and homozygous individuals with neuronal ceroid lipofuscinosis (ClinVar, LOVD, PMID: 10330339; 31489614; 30771299; 32329550; 23418007; 32855042, Nunes, A. et al. (2020)). (SP) 0901 - This variant has strong evidence for segregation with disease (PMID: 23418007; 31489614). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Individuals either compound heterozygous or homozygous for this variant, have been consistently demonstrated to have reduced Tpp1 enzyme activity, considered to be the gold standard of diagnosing individuals with neuronal ceroid lipofuscinosis 2 (PMID: 10330339, PMID: 32329550, PMID: 23418007, Nunes, A. et al. (2020)). (SP) 1102 - Strong phenotype match for this individual. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Revvity Omics, Revvity RCV001215564 SCV003820954 uncertain significance not provided 2020-03-17 criteria provided, single submitter clinical testing
Natera, Inc. RCV000668623 SCV002094880 likely pathogenic Neuronal ceroid lipofuscinosis 2 2020-11-28 no assertion criteria provided clinical testing

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