Submissions for variant NM_006493.4(CLN5):c.524G>A (p.Trp175Ter)

gnomAD frequency: 0.00004  dbSNP: rs386833980

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000049957	SCV000221061	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2015-01-22	criteria provided, single submitter	literature only
GeneDx	RCV000187071	SCV000240646	likely pathogenic	not provided	2019-01-03	criteria provided, single submitter	clinical testing	A published W224X variant that is likely pathogenic has been identified in the CLN5 gene. The W224X nonsense variant in the CLN5 gene has been reported previously in three individuals with juvenile neuronal ceroid lipofuscinosis (NCL), who also harbored a second variant in the CLN5 gene, however phase was not established. (Xin et al., 2010; Starpoli et al., 2012). The W224X variant is predicted to cause loss of normal protein function through protein truncation. The W224X variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Invitae	RCV000818212	SCV000958813	pathogenic	Neuronal ceroid lipofuscinosis	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp224*) in the CLN5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 184 amino acid(s) of the CLN5 protein. This variant is present in population databases (rs386833980, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with neuronal ceroid lipofuscinosis (NCL) (PMID: 20157158). ClinVar contains an entry for this variant (Variation ID: 56544). This variant disrupts the C-terminus of the CLN5 protein. Other variant(s) that disrupt this region (p.Trp379*, p.Glu352*, p.Tyr342*) have been observed in individuals with CLN5-related conditions (PMID: 19201763, 23374165, 26342652). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000187071	SCV001713645	pathogenic	not provided	2019-04-16	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2, PP4
Genome-Nilou Lab	RCV000049957	SCV001977484	likely pathogenic	Neuronal ceroid lipofuscinosis 5	2021-08-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000818212	SCV002570816	pathogenic	Neuronal ceroid lipofuscinosis	2022-07-25	criteria provided, single submitter	clinical testing	Variant summary: CLN5 c.524G>A (p.Trp175X) 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 classified as pathogenic via ClinVar. The variant allele was found at a frequency of 1.6e-05 in 251446 control chromosomes. c.524G>A has been reported in the literature in individuals affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease; eg. Xin_2010, Staropoli_2012, Luo_2020, etc.). These data indicate that the variant may be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000049957	SCV003818741	pathogenic	Neuronal ceroid lipofuscinosis 5	2022-10-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000049957	SCV004214367	pathogenic	Neuronal ceroid lipofuscinosis 5	2023-10-22	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049957	SCV000082366	probable-pathogenic	Neuronal ceroid lipofuscinosis 5		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.