ClinVar Miner

Submissions for variant NM_006493.4(CLN5):c.775_776AT[1] (p.Phe260fs) (rs786204644)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169429 SCV000220840 likely pathogenic Neuronal ceroid lipofuscinosis 5 2014-10-27 criteria provided, single submitter literature only
GeneDx RCV000413943 SCV000491175 likely pathogenic not provided 2016-05-02 criteria provided, single submitter clinical testing The c.924_925delAT variant in the CLN5 gene has been reported in association with neuronal ceroidlipofuscinosis (Perez-Poyato et al., 2012, article in Spanish, could not be evaluated). The variantcauses a frameshift starting with codon Phenylalanine 309, changes this amino acid to a Serine residueand creates a premature Stop codon at position 12 of the new reading frame, denotedp.Phe309SerfsX12. This variant is predicted to replace the last 99 amino acids with 11 incorrectones. Therefore, this variant is likely pathogenic; however the possibility that it is benign cannot becompletely excluded.
Invitae RCV000468638 SCV000549225 pathogenic Neuronal ceroid lipofuscinosis 2019-11-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe309Serfs*12) in the CLN5 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs769059034, ExAC 0.03%). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with neuronal ceroid lipofuscinosis (PMID: 22532218 [in Spanish]). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 189038). A different frameshift mutation (c.1175_1176delAT) downstream of this position is reported to be pathogenic (PMID: 9662406). This indicates that this frameshift mutation also disrupt residues that are important for CLN5 protein function. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000169429 SCV000919231 likely pathogenic Neuronal ceroid lipofuscinosis 5 2018-07-12 criteria provided, single submitter clinical testing Variant summary: CLN5 c.924_925delAT (p.Phe309SerfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/246098 control chromosomes (in gnomAD), exclusively observed in the Latino subpopulation with a frequency of 0.00024, which does not exceed the estimated maximal expected allele frequency of a pathogenic CLN5 variant (0.0034). c.924_925delAT has been reported in the literature in a Spanish child affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Perez-Poyato_2012 [Article in Spanish]), with an other truncating CLN5 variant (c.507delT) in trans. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One of these laboratories classified the variant as pathogenic, and the other as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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