ClinVar Miner

Submissions for variant NM_003978.5(PSTPIP1):c.1222G>A (p.Val408Ile) (rs750572947)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494336 SCV000582310 uncertain significance not provided 2017-05-08 criteria provided, single submitter clinical testing The V408I 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 8/14702 (0.054%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). V408I is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is 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.
Invitae RCV001037345 SCV001200755 uncertain significance Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2020-09-01 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 408 of the PSTPIP1 protein (p.Val408Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs750572947, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with symptoms consistent with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome (PMID: 31443670). However, in those individuals a homozygous variant in a different gene was also detected suggesting that this variant is not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 429683). 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: Possibly 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.

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