Submissions for variant NM_006493.4(CLN5):c.1045C>T (p.Pro349Ser)

gnomAD frequency: 0.00026  dbSNP: rs41287036

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000116753	SCV000150727	uncertain significance	not provided	2014-01-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000116753	SCV000240631	uncertain significance	not provided	2021-12-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Illumina Laboratory Services, Illumina	RCV000319549	SCV000384732	uncertain significance	Neuronal Ceroid-Lipofuscinosis, Dominant/Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000543328	SCV000628960	uncertain significance	Neuronal ceroid lipofuscinosis	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 398 of the CLN5 protein (p.Pro398Ser). This variant is present in population databases (rs41287036, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 128780). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLN5 protein function. 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.
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System	RCV000678298	SCV000804356	uncertain significance	Neuronal ceroid lipofuscinosis 5	2018-02-21	criteria provided, single submitter	provider interpretation	This is a 17 year old male with an adolescent-onset movement disorder, abnormal EEG, global developmental delay, intellectual disbility, dysarthria, behavior issues, and history of prematurity and fetal hydrops. Brain MRI was normal. He was prescribed glasses for a mild refractive error. The p.Pro398Ser variant is present in gnomAD non-Finnish European population at 0.018%. Computational prediction models are inconsistent. No additional variants were identified in the CLN5 gene.
Illumina Laboratory Services, Illumina	RCV000678298	SCV001266527	uncertain significance	Neuronal ceroid lipofuscinosis 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genome-Nilou Lab	RCV000678298	SCV002027079	uncertain significance	Neuronal ceroid lipofuscinosis 5	2021-09-05	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000678298	SCV001460327	uncertain significance	Neuronal ceroid lipofuscinosis 5	2020-04-16	no assertion criteria provided	clinical testing