Submissions for variant NM_001353345.2(SETD1B):c.22dup (p.His8fs)

dbSNP: rs777278685

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002723694	SCV003560918	pathogenic	Inborn genetic diseases	2024-01-08	criteria provided, single submitter	clinical testing	The c.22dupC (p.H8Pfs*30) alteration, located in exon 1 (coding exon 1) of the SETD1B gene, consists of a duplication of C at position 22, causing a translational frameshift with a predicted alternate stop codon after 30 amino acids. 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 determined to be the result of a de novo mutation in two individuals with features consistent with SETD1B-related neurodevelopmental disorder (Weerts, 2021). Based on the available evidence, this alteration is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003388163	SCV004099864	pathogenic	Intellectual developmental disorder with seizures and language delay	2023-09-15	criteria provided, single submitter	clinical testing	Variant summary: SETD1B c.22dupC (p.His8ProfsX30) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 9.5e-05 in 136830 control chromosomes, however, this finding should be interpretted with caution as metrics indicate poor quality at this region in the gnomAD database, suggesting this data is unreliable. c.22dupC has been reported in the literature in the heterozygous state in two unrelated individuals affected with Intellectual Developmental Disorder With Seizures And Language Delay, where in both cases it was found to be de novo (Weerts_2021). These data indicate that the variant is very likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34345025). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV003389088	SCV004101256	pathogenic	Neurodevelopmental disorder	2023-05-17	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV003388163	SCV004698064	pathogenic	Intellectual developmental disorder with seizures and language delay	2024-02-29	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS2,PS4_MOD
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV003388163	SCV004801670	pathogenic	Intellectual developmental disorder with seizures and language delay	2024-03-20	criteria provided, single submitter	clinical testing	This variant has been identified by standard clinical testing. de novo in a male patient with speech-related developmental disorder, myoclonic atonic therapy-refractory epilepsy and behavioral problems. Selected ACMG criteria: Pathogenic (I):PP5;PS2;PVS1
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV003388163	SCV005400550	pathogenic	Intellectual developmental disorder with seizures and language delay	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, 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 with seizures and language delay (MIM#619000). (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) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in heterozygous de novo individuals with SETD1B-related symptoms (PMID: 34345025). (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
Solve-RD Consortium	RCV003388163	SCV005199991	likely pathogenic	Intellectual developmental disorder with seizures and language delay	2022-06-01	no assertion criteria provided	provider interpretation	Variant confirmed as disease-causing by referring clinical team