ClinVar Miner

Submissions for variant NM_006846.4(SPINK5):c.1960C>T (p.Arg654Cys)

gnomAD frequency: 0.00041  dbSNP: rs199567491
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522160 SCV000616883 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing The R654C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 22/24006 (0.09%) alleles from individuals of African background in the ExAC dataset (Lek et al., 2016). The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV000634467 SCV000755778 uncertain significance Netherton syndrome 2022-08-16 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 654 of the SPINK5 protein (p.Arg654Cys). This variant is present in population databases (rs199567491, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with SPINK5-related conditions. ClinVar contains an entry for this variant (Variation ID: 449102). 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"). 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.
Breakthrough Genomics, Breakthrough Genomics RCV000522160 SCV005188658 uncertain significance not provided criteria provided, single submitter not provided

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