Submissions for variant NM_001371596.2(MFSD8):c.362A>G (p.Tyr121Cys)

dbSNP: rs118203978

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000188166	SCV000241773	uncertain significance	not provided	2022-05-20	criteria provided, single submitter	clinical testing	Identified in a cohort of individuals with epilepsy and neurodevelopmental disorders; however, detailed clinical and segregation data was not provided (Lindy et al., 2018); Published functional studies demonstrate the Y121C variant does not have an effect on protein localization (Sharifi et al, 2010); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20826447, 29655203, 18850119)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001059	SCV000639423	uncertain significance	Neuronal ceroid lipofuscinosis 7	2021-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine with cysteine at codon 121 of the MFSD8 protein (p.Tyr121Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with late infantile neuronal ceroid lipofuscinoses in 3 siblings (PMID: 18850119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1004). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect MFSD8 function (PMID: 20826447). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700177	SCV005202706	pathogenic	Neuronal ceroid lipofuscinosis	2024-07-10	criteria provided, single submitter	clinical testing	Variant summary: MFSD8 c.362A>G (p.Tyr121Cys) 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 was absent in 251318 control chromosomes. c.362A>G has been reported in the literature in multiple homozygous individuals affected with Late Infantile Neuronal Ceroid-Lipofuscinosis (Batten Disease) (Stogmann_2009) and in an individual with clinical features of Neuronal Ceroid-Lipofuscinosis with an unspecified second allele (Lindy_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Sharifi_2010). The following publications have been ascertained in the context of this evaluation (PMID: 29655203, 20826447, 18850119). ClinVar contains an entry for this variant (Variation ID: 1004). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000001059	SCV000021209	pathogenic	Neuronal ceroid lipofuscinosis 7	2009-02-01	no assertion criteria provided	literature only