ClinVar Miner

Submissions for variant NM_152778.3(MFSD8):c.362A>G (p.Tyr121Cys) (rs118203978)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188166 SCV000241773 pathogenic not provided 2014-02-13 criteria provided, single submitter clinical testing p.Tyr121Cys (TAT>TGT): c.362 A>G in exon 5 of the MFSD8 gene (NM_152778.2)The Tyr121Cys mutation has been reported previously as a homozygous mutation in three siblings with NCL (Stogmann et al., 2009). This mutation is a non-conservative amino acid substitution as these residues differ in properties that are likely to impact the secondary structure of the protein. Additionally, it was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in CHILD-EPI panel(s).
Invitae RCV000001059 SCV000639423 uncertain significance Neuronal ceroid lipofuscinosis 7 2018-09-25 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 variant has been reported to segregate with late infantile neuronal ceroid lipofuscinoses in 3 siblings from a single family (PMID: 18850119). ClinVar contains an entry for this variant (Variation ID: 1004). Experimental studies have found that this variant does not interfere with the proper localization of MFSD8 in transfected cells, but this result does not preclude other undetected effects of this variant (PMID: 20826447). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare variant that has been reported to segregate with disease in a single family. However, in the absence of additional genetic or functional data, its role in disease cannot be conclusively established. For these reasons, this change has been classified as a Variant of Uncertain Significance.
OMIM RCV000001059 SCV000021209 pathogenic Neuronal ceroid lipofuscinosis 7 2009-02-01 no assertion criteria provided literature only

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