ClinVar Miner

Submissions for variant NM_001371596.2(MFSD8):c.706C>T (p.Arg236Cys)

gnomAD frequency: 0.00001  dbSNP: rs758002981
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188173 SCV000241780 uncertain significance not provided 2012-08-29 criteria provided, single submitter clinical testing p.Arg236Cys (CGT>TGT):c.706 C>T in exon 8 of the MFSD8 gene (NM_152778.2)The Arg236Cys missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The NHLBI ESP Exome Variant Project has not identified Arg236Cys in approximately 6500 individuals of European or African American ancestry, indicating that it is not a common benign variant in these populations. Arg236Cys is a non-conservative amino acid substitution as a positively charged Arginine residue is replaced by an uncharged Cysteine residue. Other missense mutations in this region of the MFSD8 protein have been reported. However, Arg236Cys alters a position that is not highly conserved and while some in silico algorithms predict Arg236Cys may be damaging to protein structure/function, another model predicts it is likely not pathogenic. Therefore, based on the current available information, it is unclear whether Arg236Cys is a disease-causing mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp RCV000808486 SCV000948596 uncertain significance Neuronal ceroid lipofuscinosis 7 2023-11-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 236 of the MFSD8 protein (p.Arg236Cys). This variant is present in population databases (rs758002981, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. ClinVar contains an entry for this variant (Variation ID: 206154). 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 not expected to disrupt MFSD8 protein function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Natera, Inc. RCV001833122 SCV002084786 uncertain significance Late-infantile neuronal ceroid lipofuscinosis 2019-11-11 no assertion criteria provided clinical testing

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