Submissions for variant NM_017882.3(CLN6):c.278C>T (p.Thr93Met)

gnomAD frequency: 0.00006  dbSNP: rs150001589

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000187115	SCV000240690	uncertain significance	not provided	2020-01-28	criteria provided, single submitter	clinical testing	Reported previously in a patient with adult-onset neuronal ceroid lipofusinosis who had a second CLN6 variant; however, information about parental testing was not provided (Kousi et al., 2012); Reported previously in a patient with suspected mitochondrial disease who was compound heterozygous for T93M and a second CLN6 variant (DeRa et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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: 30561534, 21990111, 24215330)
Invitae	RCV000803649	SCV000943530	uncertain significance	Neuronal ceroid lipofuscinosis	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 93 of the CLN6 protein (p.Thr93Met). This variant is present in population databases (rs150001589, gnomAD 0.005%). This missense change has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21990111, 24215330, 30561534). ClinVar contains an entry for this variant (Variation ID: 205183). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000187115	SCV001247327	likely pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804924	SCV002051409	uncertain significance	not specified	2021-12-28	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.278C>T (p.Thr93Met) results in a non-conservative amino acid change in 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 2.8e-05 in 251478 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.278C>T has been reported in the literature in individuals affected with mitochondrial disorder (DaRe_2013), Parkinson's disease (Robak_2017), or Neuronal Ceroid-Lipofuscinosis (Batten Disease, Berkovic_2019). These reports do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=1, VUS n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.