ClinVar Miner

Submissions for variant NM_000310.3(PPT1):c.536G>A (p.Arg179His) (rs370069880)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000188721 SCV000242345 uncertain significance not provided 2016-03-31 criteria provided, single submitter clinical testing The c.536 G>A nucleotide substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. Multiple in vivo is unknown. If c.536 G>A does not alter splicing in all or a portion of transcripts, then it will result in the Arg179His missense variant of unknown significance. This amino acid substitution is conservative since Arginine and Histidine are both positively charged amino acids, and it alters a position that is not conserved in the PPT1 protein or in related proteins. Multiple in silico models predict that the Arg179His missense substitution is likely benign. Based on the currently available information, it is unclear whether c.536 G>A is a disease-causing mutation or a rare benign variant.
Invitae RCV000476535 SCV000550821 uncertain significance Ceroid lipofuscinosis neuronal 1 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 179 of the PPT1 protein (p.Arg179His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. It also falls at the last nucleotide of exon 5 of the PPT1 coding sequence. This variant is present in population databases (rs370069880, ExAC 0.009%) but has not been reported in the literature in individuals with a PPT1-related disease. ClinVar contains an entry for this variant (Variation ID: 206648). 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 histidine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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