ClinVar Miner

Submissions for variant NM_152778.3(MFSD8):c.1235C>T (p.Pro412Leu) (rs267607235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000720090 SCV000850966 likely pathogenic Seizures 2016-04-11 criteria provided, single submitter clinical testing The p.P412L variant (also known as c.1235C>T), located in coding exon 11 of the MFSD8 gene, results from a C to T substitution at nucleotide position 1235. The proline at codon 412 is replaced by leucine, an amino acid with similar properties. A study analyzing the functional proteolytic cleavage activity of this gene in COS-7 cellsfound that this variant resulted in increased proteolytic cleavage oftheCLN7 proteinin lysosomespresumably resulting in a non-functional protein(Steenhuis et al. Biochim Biophys Acta. 2012;1822 (10):1617-28). In another study, the p.P412L variant (referred to as c.1398C>T) was identified in a homozygous state in a consanguineous Saudi Arabian family with three affected children. The index case was a 10-year-old boy whodeveloped progressive blindness, focal seizures with secondary generalized tonic clonic convulsions, and progressive decline in cognitive function in association with the Turkish variant of late-infantile Neuronal Ceroid Lipofuscinosis,characterized by a later age of onset and a more severe seizure phenotype (Aldahmesh et al. Neurogenetics. 2009;10:307-311). This variant was previously reported in the SNPDatabase as rs267607235. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6,503 samples (13,006 alleles) with coverage at this position.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000001060 SCV001227174 pathogenic Neuronal ceroid lipofuscinosis 7 2019-06-26 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 412 of the MFSD8 protein (p.Pro412Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs267607235, ExAC 0.02%). This variant has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been observed to segregate with neuronal ceroid lipofuscinosis in a family (PMID: 19277732). ClinVar contains an entry for this variant (Variation ID: 1005). This variant has been reported to affect MFSD8 protein function (PMID:22668694). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000001060 SCV001519858 likely pathogenic Neuronal ceroid lipofuscinosis 7 2020-06-09 criteria provided, single submitter clinical testing This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
OMIM RCV000001060 SCV000021210 pathogenic Neuronal ceroid lipofuscinosis 7 2009-10-01 no assertion criteria provided literature only

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