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

gnomAD frequency: 0.00004  dbSNP: rs374681194

Total submissions: 5

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
Labcorp Genetics (formerly Invitae), Labcorp	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