Submissions for variant NM_017882.3(CLN6):c.150C>G (p.Tyr50Ter)

gnomAD frequency: 0.00002  dbSNP: rs154774640

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000058908	SCV000568366	pathogenic	not provided	2024-11-15	criteria provided, single submitter	clinical testing	Reported previously in a patient with a clinical diagnosis of Kufs disease who was also heterozygous for two missense substitutions in the CLN6 gene, although no further clinical details were provided and parental testing was not performed to determine the phase of the three variants (PMID: 21549341); Reported previously as a pathogenic variant in a cohort of patients referred for epilepsy genetic testing; however, no specific clinical information was provided (PMID: 31440721); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 31440721, 26075876, 33024953, 21549341)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000702360	SCV000831212	pathogenic	Neuronal ceroid lipofuscinosis	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr50*) in the CLN6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLN6 are known to be pathogenic (PMID: 19135028). This variant is present in population databases (rs154774640, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinosis (PMID: 21549341, 26075876). ClinVar contains an entry for this variant (Variation ID: 68094). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000702360	SCV003844709	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-02-02	criteria provided, single submitter	clinical testing	Variant summary: CLN6 c.150C>G (p.Tyr50X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been associated with Neuronal Ceroid Lipofuscinosis (NCL) in HGMD. The variant allele was found at a frequency of 8e-06 in 251404 control chromosomes. c.150C>G has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (DiFruscio_2015), and specifically in Kufs disease, a subtype of NCL (Arsov_2011, Talbot_2020). 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. Laboratories classified the variant as pathogenic (n=1) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000058908	SCV004703339	pathogenic	not provided	2024-01-01	criteria provided, single submitter	clinical testing	CLN6: PVS1, PM2, PM3
SNPedia	RCV000058908	SCV000090429	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000668229	SCV000792797	likely pathogenic	Ceroid lipofuscinosis, neuronal, 6A	2017-07-14	no assertion criteria provided	clinical testing