Submissions for variant NM_001371596.2(MFSD8):c.1444C>T (p.Arg482Ter)

gnomAD frequency: 0.00003  dbSNP: rs724159971

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000256110	SCV000322271	pathogenic	not provided	2021-12-18	criteria provided, single submitter	clinical testing	Reported in association with variant late-infantile neuronal ceroid lipofucinosis (Aiello et al., 2009; Kousi et al., 2012).; Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 37 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22668694, 21990111, 19177532, 28708303, 31105743, 33726816)
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000149777	SCV000586765	pathogenic	Neuronal ceroid lipofuscinosis 7	2017-01-06	criteria provided, single submitter	clinical testing	peripheric neuropathy; global cerebral atrophy; epilepsy (myoclonia); severe regression of acquisitions starting at 3 years old
Labcorp Genetics (formerly Invitae), Labcorp	RCV000149777	SCV000762058	pathogenic	Neuronal ceroid lipofuscinosis 7	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg482*) in the MFSD8 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the MFSD8 protein. This variant is present in population databases (rs724159971, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with variant-late infantile neuronal ceroid lipofuscinosis (VL-NCL) and neuronal ceroid lipofuscinosis (PMID: 19177532, 25976102, 28708303; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162382). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763521	SCV000894333	likely pathogenic	Neuronal ceroid lipofuscinosis 7; Macular dystrophy with central cone involvement	2018-10-31	criteria provided, single submitter	clinical testing
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000149777	SCV001554474	pathogenic	Neuronal ceroid lipofuscinosis 7	2021-04-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002390318	SCV002697903	likely pathogenic	Inborn genetic diseases	2018-11-29	criteria provided, single submitter	clinical testing	The p.R482* variant (also known as c.1444C>T), located in coding exon 12 of the MFSD8 gene, results from a C to T substitution at nucleotide position 1444. This changes the amino acid from an arginine to a stop codon within coding exon 12. Premature stop codons are typically deleterious in nature, however, this stop codon occurs at the 3' terminus of MFSD8, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 37 amino acids of the protein. The exact functional impact of these removed amino acids is unknown at this time. This alteration has been reported in children with variant-late infantile form of NCL (v-LINCL); in one case, a second pathogenic variant was detected however parental testing was not performed to confirm phase (Aiello C et al. Hum. Mutat., 2009 Mar;30:E530-40); in another, the p.R482* variant was confirmed in trans with a second disease causing allele (Chérot E et al. Clin. Genet., 2018 Mar;93:567-576). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
OMIM	RCV000149777	SCV000196590	pathogenic	Neuronal ceroid lipofuscinosis 7	2009-03-01	no assertion criteria provided	literature only