ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.755G>A (p.Arg252His)

gnomAD frequency: 0.00004  dbSNP: rs374681194
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187105 SCV000240680 uncertain significance not provided 2019-06-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Previously reported two patients with suspected neuronal ceroid lipofuscinosis (NCL); the first patient also had a frameshift variant in CLN6; however, phase was unknown and functional/EM studies were not performed; the second patient did not have a second CLN6 variant clearly identified but EM studies were consistent with the diagnosis of NCL (Kousi et al., 2012); This variant is associated with the following publications: (PMID: 21990111)
Counsyl RCV000671648 SCV000796641 uncertain significance Ceroid lipofuscinosis, neuronal, 6A 2017-12-20 criteria provided, single submitter clinical testing
Invitae RCV001083020 SCV001003471 likely benign Neuronal ceroid lipofuscinosis 2024-01-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV002390489 SCV002675203 uncertain significance Inborn genetic diseases 2018-03-13 criteria provided, single submitter clinical testing The p.R252H variant (also known as c.755G>A), located in coding exon 7 of the CLN6 gene, results from a G to A substitution at nucleotide position 755. The arginine at codon 252 is replaced by histidine, an amino acid with highly similar properties. This alteration has been detected in two individuals with suspected diagnoses of neuronal ceroid lipofuscinosis (NCL). The first individual also carried the p.F185Lfs*17 CLN6 alteration; however, phase was not confirmed. The second individual did not have a second CLN6 alteration identified (Kousi M et al. Hum. Mutat., 2012 Jan;33:42-63; Kohan R et al. Biochim. Biophys. Acta, 2015 Oct;1852:2301-11). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Translational Research Program on Neuronal Ceroid Lipofuscinosis, Center for the Study of Inborn Errors of Metabolism RCV000671648 SCV000804310 pathogenic Ceroid lipofuscinosis, neuronal, 6A no assertion criteria provided research Late Infantile NCL

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