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

dbSNP: rs1553641476

Total submissions: 7

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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000523957	SCV003459368	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	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. This variant is not present in population databases (gnomAD no frequency). 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).
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
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000987091	SCV005198221	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2024-09-10	criteria provided, single submitter	clinical testing	ACMG criteria used: PVS1, PS2 (internal data), PM2.
Molecular Genetics laboratory, Necker Hospital	RCV000523957	SCV004031282	pathogenic	not provided	2022-01-03	no assertion criteria provided	clinical testing