ClinVar Miner

Submissions for variant NM_001372044.2(SHANK3):c.4874_4878dup (p.Pro1627fs)

dbSNP: rs1603447373
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes RCV000782013 SCV000920475 likely pathogenic not provided 2017-11-22 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000782013 SCV001247854 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing SHANK3: PVS1:Strong, PM2, PS2:Moderate, PS4:Moderate
GeneDx RCV000782013 SCV001776415 pathogenic not provided 2021-10-27 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation as the last 180 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32050889)
Ambry Genetics RCV004027330 SCV004946656 pathogenic Inborn genetic diseases 2024-01-02 criteria provided, single submitter clinical testing The c.4649_4653dupGCAGC (p.P1552Afs*14) alteration, located in exon 22 (coding exon 22) of the SHANK3 gene, consists of a duplication of GCAGC at position 4649, causing a translational frameshift with a predicted alternate stop codon after 14 amino acids. This alteration occurs at the 3' terminus of the SHANK3 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 11% of the protein. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function, and a significant portion of the protein is affected (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in one individual with features consistent with Phelan-McDermid syndrome (Kohlenberg, 2020). Based on the available evidence, this alteration is classified as pathogenic.

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