ClinVar Miner

Submissions for variant NM_000391.4(TPP1):c.1266G>C (p.Gln422His) (rs121908200)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189782 SCV000243430 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The Q422H variant in the TPP1 gene has been previously reported in association with neuronal ceroid lipofuscinoses 2 (CLN2) and was present on 7% of disease alleles in one study of 74 families with the late-infantile presentation of CLN2 (Sleat et al., 1999). This variant results in a TPP1 proenzyme with severely compromised secretion from the endoplasmic reticulum to the Golgi apparatus (Walus et al., 2010). The Q422H variant is observed in 2/33580 (0.006%) alleles from individuals of Latino background in large population cohorts (Lek et al., 2016). The Q422H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, this variant is considered a pathogenic variant.
Ambry Genetics RCV000210643 SCV000262861 pathogenic Inborn genetic diseases 2013-06-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000059620 SCV000611328 pathogenic Ceroid lipofuscinosis neuronal 2 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000529451 SCV000628896 pathogenic Neuronal ceroid lipofuscinosis 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 422 of the TPP1 protein (p.Gln422His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide and within the consensus splice site of exon 10 of the TPP1 coding sequence. This variant is present in population databases (rs121908200, ExAC 0.001%). This variant is reported in several families with late infantile neuronal ceroid lipofuscinosis (LINCL) and found to be on the opposite allele (in trans) of five different pathogenic TPP1 variants (PMID: 10330339, 25356970, 12376936, 22612257). ClinVar contains an entry for this variant (Variation ID: 68738). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Experimental studies of this missense change in cell culture suggest that this variant results in decreased expression of the mature TPP1 protein (PMID: 15317752, 20340139). This correlates with decreased enzymatic activity in affected individuals (PMID: 10330339). In summary, this variant is a rare missense change that results in decreased expression and activity of the TPP1 protein. This variant is absent from the general population and recurrent in individuals with TPP1-related disease. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000529451 SCV001337989 pathogenic Neuronal ceroid lipofuscinosis 2020-01-27 criteria provided, single submitter clinical testing Variant summary: TPP1 c.1266G>C (p.Gln422His) results in a non-conservative amino acid change located in the Sedolisin domain (IPR030400) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251454 control chromosomes. c.1266G>C has been reported in the literature in multiple individuals from diverse ethnicities affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (example, Sleat_1999). 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 function. The most pronounced variant effect results in abnormal processing, impaired trafficking and impaired secretion of TPPI with non detectable levels of TPPI activity in vitro (Walus_2010). Three 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
UniProtKB/Swiss-Prot RCV000059620 SCV000091186 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252369 SCV001428124 likely pathogenic Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia 2019-01-01 no assertion criteria provided clinical testing

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