Submissions for variant NM_006493.4(CLN5):c.188G>A (p.Arg63His)

gnomAD frequency: 0.00001  dbSNP: rs104894386

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000698933	SCV000827624	pathogenic	Neuronal ceroid lipofuscinosis	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 112 of the CLN5 protein (p.Arg112His). This variant is present in population databases (rs104894386, gnomAD 0.003%). This missense change has been observed in individuals with juvenile onset neuronal ceroid lipofuscinosis (PMID: 15728307, 28542837, 30078242). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2567). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLN5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CLN5 function (PMID: 20052765). This variant disrupts the p.Arg112 amino acid residue in CLN5. Other variant(s) that disrupt this residue have been observed in individuals with CLN5-related conditions (PMID: 30078242), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000002676	SCV001530515	likely pathogenic	Neuronal ceroid lipofuscinosis 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000002676	SCV001977461	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-10	criteria provided, single submitter	clinical testing
GeneDx	RCV003128567	SCV003805402	pathogenic	not provided	2023-02-06	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect as the R112H variant produces a protein unable to exit the endoplasmic reticulum (Schmiedt et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); 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: 21990111, 15728307, 33792748, 30264640, 28542837, 30078242, 32983231, 20052765)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000698933	SCV004037644	likely pathogenic	Neuronal ceroid lipofuscinosis	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.188G>A (p.Arg63His), also referred to as p.Arg112His, 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 8e-06 in 251186 control chromosomes (gnomAD). c.188G>A has been reported in the literature in the homozygous state in two siblings and in at least one other unrelated individual affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) (e.g. Pineda-Trujilo_2005, Zhou_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating that the variant protein primarily localizes to the ER as opposed to the lysosome, however, it does not allow convincing conclusions about the variant effect (Schmiedt_2010). Other variants affecting the same amino acid (i.e. p.Arg63Cys, p.Arg63Pro) have been reported in association with Neuronal Ceroid-Lipofuscinosis in the HGMD database, suggesting Arg63 may be important for protein function, but this has yet to be determined conclusively. The following publications have been ascertained in the context of this evaluation (PMID: 15728307, 20052765, 30078242). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000002676	SCV000022834	pathogenic	Neuronal ceroid lipofuscinosis 5	2005-02-22	no assertion criteria provided	literature only
Natera, Inc.	RCV000698933	SCV002087951	likely pathogenic	Neuronal ceroid lipofuscinosis	2021-04-09	no assertion criteria provided	clinical testing