ClinVar Miner

Submissions for variant NM_003978.5(PSTPIP1):c.146C>T (p.Ala49Val) (rs756426938)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521154 SCV000620445 uncertain significance not provided 2017-09-05 criteria provided, single submitter clinical testing The A49V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). A49V 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, and 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.
Invitae RCV001209843 SCV001381295 uncertain significance Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2019-06-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 49 of the PSTPIP1 protein (p.Ala49Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs756426938, ExAC 0.007%). This variant has not been reported in the literature in individuals with PSTPIP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451711). 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001209843 SCV001472154 uncertain significance Pyogenic arthritis-pyoderma gangrenosum-acne syndrome 2019-09-15 criteria provided, single submitter clinical testing The PSTPIP1 c.146C>T; p.Ala49Val variant (rs756426938), to our knowledge, is not reported in the medical literature but is reported in an individual with an autoinflammatory disease in a gene-specific database (see link below). The variant is reported in the ClinVar database (Variation ID: 451711) and in the general population with an overall allele frequency of 0.0017% (4/230,060 alleles) in the Genome Aggregation Database. The alanine at this position is moderately conserved and computational analyses (SIFT: Tolerated, PolyPhen-2: Possibly Damaging) predict conflicting effects of this variant on protein structure/function. Due to limited information, the clinical significance of this variant cannot be determined. References: Link to Infevers database:

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