ClinVar Genomic variation as it relates to human health

Variant summary: MFSD8 c.1361T>C (p.Met454Thr) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250440 control chromosomes, predominantly at a frequency of 0.00082 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00082 vs 0.00094), allowing no conclusion about variant significance. c.1361T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with retinal disease (e.g. Carss_2017, Khan_2017, Zare-Abdollahi_2019). It was also reported in cis with another variant in homozygous siblings affected with late-infantile Neuronal Ceroid-Lipofuscinosis (Patino_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while two other submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.

Reported with a second variant, phase unknown, in an individual with retinal disease (Abdollahi et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 28041643, 28586915, 25333361, 31006324, 32037395, 35457110, 32581362)

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 454 of the MFSD8 protein (p.Met454Thr). This variant is present in population databases (rs559155109, gnomAD 0.08%). This missense change has been observed in individuals with retinal dystrophy and neuronal ceroid lipofuscinosis (PMID: 25333361, 28041643, 28586915). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418295). 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) performed at Invitae indicates that this missense variant is expected to disrupt MFSD8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

The p.M454T variant (also known as c.1361T>C), located in coding exon 12 of the MFSD8 gene, results from a T to C substitution at nucleotide position 1361. The methionine at codon 454 is replaced by threonine, an amino acid with similar properties. This variant has been identified in the homozygous state and in trans with a MFSD8 likely pathogenic variant in multiple individuals with clinical features of MFSD8-associated disease (Patiño LC et al. PLoS One, 2014 Oct;9:e109576; Khan KN et al. Invest Ophthalmol Vis Sci, 2017 06;58:2906-2914; Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145; Zampaglione E et al. Genet Med, 2020 06;22:1079-1087; Carss KJ et al. Am J Hum Genet, 2017 01;100:75-90). In addition, this alteration has been shown to co-segregate with disease in multiple individuals from two families who have clinical features consistent with MFSD8-related disorders (Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

The observed missense variant c.1361T>C (p.Met454Thr) in MFSD8 gene has been reported previously in both homozygous and compound heterozygous state in multiple individuals affected with MFSD8-associated retinal disorder (Carss et al. 2017; Khan et al. 2017; Zare-Abdollahi et al. 2019). This variant is reported to be segregating with the disease (Zare-Abdollahi et al. 2019). This variant is identified as a founder variant of South-Asian origin (Khan et al. 2017). The p.Met454Thr variant is present with an allele frequency of 0.01% on gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic. Multiple lines of computational evidence (SIFT - damaging; Polyphen - probably damaging; MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on MFSD8 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 454 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.