Submissions for variant NM_001371596.2(MFSD8):c.1235C>T (p.Pro412Leu)

gnomAD frequency: 0.00001  dbSNP: rs267607235

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002316184	SCV000850966	likely pathogenic	Inborn genetic diseases	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 cells found that this variant resulted in increased proteolytic cleavage of the CLN7 protein in lysosomes presumably 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 who developed 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001060	SCV001227174	pathogenic	Neuronal ceroid lipofuscinosis 7	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 412 of the MFSD8 protein (p.Pro412Leu). This variant is present in population databases (rs267607235, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 19277732; internal data). 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: 1005). Invitae Evidence 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 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 MFSD8 protein function. Experimental studies have shown that this missense change affects MFSD8 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].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222334	SCV002500268	pathogenic	Neuronal ceroid lipofuscinosis	2022-03-01	criteria provided, single submitter	clinical testing	Variant summary: MFSD8 c.1235C>T (p.Pro412Leu) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of 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 2e-05 in 251370 control chromosomes (gnomAD). c.1235C>T has been reported in the literature in multiple individuals/families affected with Neuronal Ceroid-Lipofuscinosis (Batten Disease) and cone-rod dystrophy (e.g. Aldahmesh_2009, Di Fruscio_2015, Zare-Abdollahi_2019). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant enhanced its proteolytic cleavage in lysosomes (Steenhuis_2012). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001060	SCV002557044	pathogenic	Neuronal ceroid lipofuscinosis 7	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine (exon 12). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (5 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif, (the junction btw transmembrane domain 10 and 9; PMID:19277732). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0802 - Moderate previous evidence of pathogenicity. This variant has been reported as homozygous and compound heterozygous in two families with neuronal ceroid lipofuscinosis and cone rod dystrophy, respectively (LOVD, ClinVar, PMID: 19277732, PMID: 31006324). (P) 0901 - Strong evidence for segregation with disease in two families (PMID: 19277732, PMID: 31006324). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Assays demonstrated that mutant protein was more readily cleaved and degraded (PMID:22668694). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV002496222	SCV002810929	likely pathogenic	Neuronal ceroid lipofuscinosis 7; Macular dystrophy with central cone involvement	2024-05-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003137482	SCV003808797	pathogenic	not provided	2023-06-28	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000001060	SCV004801219	likely pathogenic	Neuronal ceroid lipofuscinosis 7	2024-03-14	criteria provided, single submitter	research
OMIM	RCV000001060	SCV000021210	pathogenic	Neuronal ceroid lipofuscinosis 7	2009-10-01	no assertion criteria provided	literature only