ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
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.
Invitae RCV000529451 SCV000628896 pathogenic Neuronal ceroid lipofuscinosis 2017-07-11 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.
UniProtKB/Swiss-Prot RCV000059620 SCV000091186 not provided Ceroid lipofuscinosis neuronal 2 no assertion provided not provided

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