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

gnomAD frequency: 0.00006  dbSNP: rs767164948

Total submissions: 6

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	Ceroid lipofuscinosis, neuronal, 6A	2017-02-17	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478655	SCV000894930	uncertain significance	Ceroid lipofuscinosis, neuronal, 6A; Ceroid lipofuscinosis, neuronal, 6B (Kufs type)	2022-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV000803026	SCV000942881	uncertain significance	Neuronal ceroid lipofuscinosis	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 243 of the CLN6 protein (p.Ala243Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282022	SCV002571874	uncertain significance	not specified	2023-09-05	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.728C>T (p.Ala243Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251116 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.728C>T has been reported in the literature in the heterozygous state in two individuals with clinical features of Neuronal Ceroid-Lipofuscinosis, with no second variant detected (Di Fruscio_2015). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 26075876). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000187103	SCV004564193	uncertain significance	not provided	2023-09-15	criteria provided, single submitter	clinical testing	The CLN6 c.728C>T; p.Ala243Val variant (rs767164948) is reported in the literature in two individuals affected with neuronal ceroid lipofuscinosis (Di Fruscio 2015). This variant is also reported in ClinVar (Variation ID: 205174) and is found in the non-Finnish European population with an allele frequency of 0.005% (6/128900 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.765). However, given the lack of clinical and functional data, the significance of this variant is uncertain at this time. References: Di Fruscio G et al. Lysoplex: An efficient toolkit to detect DNA sequence variations in the autophagy-lysosomal pathway. Autophagy. 2015;11(6):928-38. PMID: 26075876.