ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.679G>A (p.Glu227Lys) (rs746753722)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000625854 SCV000746423 pathogenic Neuronal ceroid lipofuscinosis 6 2017-12-03 criteria provided, single submitter clinical testing
Invitae RCV000799881 SCV000939564 uncertain significance Neuronal ceroid lipofuscinosis 2019-04-25 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 227 of the CLN6 protein (p.Glu227Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs746753722, ExAC 0.01%). This variant has not been reported in the literature in individuals with CLN6-related disease. ClinVar contains an entry for this variant (Variation ID: 522701). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Institute Rare Disease Group, Broad Institute RCV000625854 SCV001132554 uncertain significance Neuronal ceroid lipofuscinosis 6 2018-11-15 criteria provided, single submitter research The homozygous p.Glu227Lys variant in CLN6 was identified by our study in one individual with Neuronal Ceroid Lipofuscinosis. This variant has been identified in the literature in the case of one affected homozygous 19-year old male (Lynch et al. 2016, PMID: 26374131). This variant has been identified in <0.01% (1/15038) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746753722). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro441Leu variant is uncertain.

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