ClinVar Miner

Submissions for variant NM_001080517.3(SETD5):c.3855dup (p.Ser1286fs)

dbSNP: rs1553641476
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523957 SCV000619370 pathogenic not provided 2022-04-03 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation, as the last 157 amino acids are replaced with 36 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28549204)
Mendelics RCV000987091 SCV001136289 likely pathogenic Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000523957 SCV003459368 pathogenic not provided 2022-02-02 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SETD5 protein in which other variant(s) (p.Ser1286Leufs*84 ) have been determined to be pathogenic (PMID: 24680889). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 450756). This variant is also known as c.3848_3849insC. This premature translational stop signal has been observed in individual(s) with non-syndromic intellectual disability (PMID: 28549204). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1286Leufs*37) in the SETD5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 157 amino acid(s) of the SETD5 protein.
Ambry Genetics RCV003362814 SCV004070458 pathogenic Inborn genetic diseases 2023-08-28 criteria provided, single submitter clinical testing The c.3855dupC (p.S1286Lfs*37) alteration, located in exon 23 (coding exon 21) of the SETD5 gene, consists of a duplication of C at position 3855, causing a translational frameshift with a predicted alternate stop codon after 37 amino acids. This alteration occurs at the 3' terminus of the SETD5 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 10% of the protein. However, premature stop codons are typically deleterious in nature 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 SETD5-related neurodevelopmental disorder (Stur, 2017). Based on the available evidence, this alteration is classified as pathogenic.
Laboratory of Medical Genetics, University of Torino RCV000987091 SCV004171089 pathogenic Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency criteria provided, single submitter clinical testing
Molecular Genetics laboratory, Necker Hospital RCV000523957 SCV004031282 pathogenic not provided 2022-01-03 no assertion criteria provided clinical testing

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