ClinVar Miner

Submissions for variant NM_017882.3(CLN6):c.728C>T (p.Ala243Val) (rs767164948)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000187103 SCV000240678 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the CLN6 gene. The A243V variant has been reported in two individuals with neuronal ceroid lipofuscinosis who were heterozygous for this change; however, a second CLN6 variant was not detected and information regarding parental testing was not provided (Di Fruscio et al., 2015). The A243V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The A243V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Counsyl RCV000665630 SCV000789783 uncertain significance Neuronal ceroid lipofuscinosis 6 2017-02-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763979 SCV000894930 uncertain significance Neuronal ceroid lipofuscinosis 6; Adult neuronal ceroid lipofuscinosis 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000803026 SCV000942881 uncertain significance Neuronal ceroid lipofuscinosis 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 243 of the CLN6 protein (p.Ala243Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs767164948, ExAC 0.003%). This variant has been observed as heterozygous in individuals affected with neuronal ceroid lipofuscinosis (PMID: 26075876). ClinVar contains an entry for this variant (Variation ID: 205174). 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.

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