Submissions for variant NM_001080517.3(SETD5):c.2302C>T (p.Arg768Ter)

dbSNP: rs864321657

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000203577	SCV001430123	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2020-02-14	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV001374941	SCV001572229	pathogenic	Neurodevelopmental disorder	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001562177	SCV001784904	pathogenic	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24859339, 25138099, 28263952, 28990276, 28191890, 23020937, 31785789, 32299058)
Daryl Scott Lab, Baylor College of Medicine	RCV000203577	SCV002072587	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2022-01-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001562177	SCV003525088	pathogenic	not provided	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg768*) in the SETD5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SETD5 are known to be pathogenic (PMID: 24680889). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of SETD5-related neurodevelopmental disorder (PMID: 25138099, 28990276). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 219198). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000203577	SCV005399718	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder, autosomal dominant 23 (MIM#615761). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (v2, v3 and v4). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic and likely-pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic or likely pathogenic in multiple individuals, including five individuals in whom the variant was de novo (PMIDs: 25138099, 23020937, 28990276, ClinVar, DECIPHER). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000203577	SCV005417891	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency		criteria provided, single submitter	clinical testing	PM2_Supporting+PS2_Supporting+PVS1+PS4_Supporting
Ambry Genetics	RCV004965329	SCV005495715	pathogenic	Inborn genetic diseases	2024-09-13	criteria provided, single submitter	clinical testing	The c.2302C>T (p.R768*) alteration, located in exon 16 (coding exon 14) of the SETD5 gene, consists of a C to T substitution at nucleotide position 2302. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 768. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with features consistent with SETD5-related neurodevelopmental disorder, and occurred de novo in at least one individual (Kuechler, 2015; Zhao, 2017). Based on the available evidence, this alteration is classified as pathogenic.
OMIM	RCV000203577	SCV000258924	pathogenic	Intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency	2012-11-10	no assertion criteria provided	literature only