Submissions for variant NM_001371596.2(MFSD8):c.1136T>C (p.Phe379Ser)

gnomAD frequency: 0.00030  dbSNP: rs191172038

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188181	SCV000241788	uncertain significance	not provided	2021-08-26	criteria provided, single submitter	clinical testing	Variant identified in at least one individual with frontotemporal lobar degeneration with functional studies suggesting variant may affect MFSD8 function by altering its intracellular trafficking (Geiger et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30382371)
Invitae	RCV000474440	SCV000548722	uncertain significance	Neuronal ceroid lipofuscinosis 7	2022-10-31	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 379 of the MFSD8 protein (p.Phe379Ser). This variant is present in population databases (rs191172038, gnomAD 0.05%). This missense change has been observed in individual(s) with cortical basal degeneration (PMID: 30382371). ClinVar contains an entry for this variant (Variation ID: 206161). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects MFSD8 function (PMID: 30382371). 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.
Illumina Laboratory Services, Illumina	RCV000474440	SCV001307854	uncertain significance	Neuronal ceroid lipofuscinosis 7	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.
New York Genome Center	RCV001256101	SCV001432888	uncertain significance	Seizure; Intellectual disability	2020-05-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321757	SCV002606037	uncertain significance	Inborn genetic diseases	2022-11-14	criteria provided, single submitter	clinical testing	The c.1136T>C (p.F379S) alteration is located in exon 12 (coding exon 11) of the MFSD8 gene. This alteration results from a T to C substitution at nucleotide position 1136, causing the phenylalanine (F) at amino acid position 379 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002500574	SCV002813274	uncertain significance	Neuronal ceroid lipofuscinosis 7; Macular dystrophy with central cone involvement	2022-05-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155112	SCV003844956	uncertain significance	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: MFSD8 c.1136T>C (p.Phe379Ser) results in a non-conservative amino acid change located in the major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00029 in 251270 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00029 vs 0.00094), allowing no conclusion about variant significance. c.1136T>C has been reported in the literature in the heterozygous state in an individual affected with corticobasal degeneration, although it was also found in healthy control individuals (Geier_2019). This report does not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). An experimental study found the variant resulted in an increased accumulation of protein at the cell surface versus WT, suggesting it may impact protein function by altering intercellular trafficking, however the clinical implications of this are still unclear (Geier_2019). Seven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001272731	SCV001454989	uncertain significance	Late-infantile neuronal ceroid lipofuscinosis	2020-01-17	no assertion criteria provided	clinical testing