ClinVar Miner

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

gnomAD frequency: 0.00002  dbSNP: rs121908200
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189782 SCV000243430 pathogenic not provided 2022-09-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect by decreased or zero activity versus wild type (Steinfeld R et al., 2004; Walus M et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25356970, 26795593, 20340139, 19038966, 10330339, 12376936, 29655203, 15317752, 22612257)
Ambry Genetics RCV000210643 SCV000262861 pathogenic Inborn genetic diseases 2013-06-26 criteria provided, single submitter clinical testing ​B1) TPP1 c.1266G>C (p.Q422H)The c.1266G>C (p.Q422H) alteration is located in exon 10 of the TPP1 gene. This alteration results from a G to C substitution at nucleotide position 1266, resulting in an amino acid substitution of glutamine (Q) for histidine (H) at codon 422.<u>​The missense change is rare in healthy cohorts</u>:Based on data from the NHLBI Exome Sequencing Project (ESP), the TPP1 c.1266G>C (p.Q422H) alteration has an overall frequency of approximately 0.01% (1/10758 total alleles studied). The C-allele was observed in 0.01% (1/7020) of European American alleles and has not been observed (0%) in African Americans among of 3738 total alleles studied. The alteration has not been observed in the homozygous state out of 5379 individuals. Allele frequency data for alterations at this nucleotide position are not currently available from the 1000 Genomes Project.<u>The altered amino acid is conserved throughout evolution</u>:The Q422 amino acid is conserved throughout vertebrate evolution.<u>The alteration is predicted deleterious by in silico models:</u>The Q422H alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses.<u>The amino acid change has been observed in affected individuals:</u>This alteration is reported in the HGMD database (Accession# CM990373). This alteration is among the most common TPP1 mutations, accounting for ~7% of mutant alleles observed in affected individuals (Sleat, 1999).Based on the available evidence, the TPP1 c.1266G>C (p.Q422H) alteration is classified as a pathogenic mutation.
Fulgent Genetics, Fulgent Genetics RCV000059620 SCV000611328 pathogenic Neuronal ceroid lipofuscinosis 2 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000189782 SCV000628896 pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 422 of the TPP1 protein (p.Gln422His). This variant also falls at the last nucleotide of exon 10, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121908200, gnomAD 0.006%). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinosis (LINCL) (PMID: 10330339, 12376936, 22612257, 25356970). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 68738). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPP1 function (PMID: 10330339). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Neuronal ceroid lipofuscinosis 2 no assertion provided not provided
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille RCV001252369 SCV001428124 likely pathogenic Autosomal recessive spinocerebellar ataxia 7 2019-01-01 no assertion criteria provided clinical testing
Natera, Inc. RCV000059620 SCV002094821 pathogenic Neuronal ceroid lipofuscinosis 2 2020-09-24 no assertion criteria provided clinical testing

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