ClinVar Genomic variation as it relates to human health

This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Multiple in silico analyses support a deleterious effect of the c.5218C>T (p.Arg1740Trp) variant on protein function. This variant has been reported as pathogenic as a heterogeneous change in ClinVar by a clinical laboratory (Accession ID: RCV000426759.1). Based on the available evidence, the c.5218C>T (p.Arg1740Trp) variant is classified as likely pathogenic.

This variant was identified as de novo (maternity and paternity confirmed).

This variant has not been previously reported or functionally characterized in the literature to our knowledge. It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Multiple in silico analyses support a deleterious effect of the c.5218C>T (p.Arg1740Trp) variant on protein function. This variant has been reported as Pathogenic as a heterozygous change by a clinical laboratory in the ClinVar databse (Variation ID: 388568). Additionally, this variant has been previously identified by our laboratory in a similarly affected individual and in multiple other similarly affected individuals. Based on the available evidence, the c.5218C>T (p.Arg1740Trp) variant is classified as Likely Pathogenic.

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31474318, 34958143, 33004838, 32710489)

The c.5218C>T (p.R1740W) alteration is located in coding exon 10 of the SETD2 gene. This alteration results from a C to T substitution at nucleotide position 5218, causing the arginine (R) at amino acid position 1740 to be replaced by a tryptophan (W). Based on data from the Genome Aggregation Database (gnomAD), the SETD2 c.5218C>T alteration was not observed, with coverage at this position. A retrospective report of this alteration showed that it was de novo in 12 patients and all were reported to have failure to thrive in infancy, feeding difficulties, severe intellectual disability, microcephaly, hypotonia, hypertelorism, micrognathia, hypoplasia of the corpus callosum and pons, cerebellar hypoplasia, and various skeletal abnormalities. Many also had congenital heart defects, genitourinary tract anomalies, hearing loss, retinal telangiectasia, and other dysmorphic features. Alterations affecting the same amino acid, p.R1740Q, were reported de novo in three patients with a milder phenotype including moderate to severe intellectual disability, low to normal head circumference, and absence of additional major congenital anomalies (Rabin, 2020). This amino acid position is highly conserved in available vertebrate species. The p.R1740W alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

A heterozygous missense variant was identified, NM_014159.6(SETD2):c.5218C>T in exon 10 of 21 of the SETD2 gene. This substitution is predicted to create a major amino acid change from an arginine to a tryptophan at position 1740 of the protein; NP_054878.5(SETD2):p.(Arg1740Trp). The arginine at this position has very high conservation (100 vertebrates, UCSC), and is situated within a constrained region. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster) and the variant is not present in the gnomAD population database. This variant has been previously reported pathogenic in a patient with cerebellar malformations (Aldinger, K. A. et al. (2019)). A different variant in the same codon resulting in a change to a glutamine has been reported as a VUS (LOVD). Testing of this patient's parents has indicated this variant is due to a de novo event. Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.

The SETD2 c.5218C>T variant is predicted to result in the amino acid substitution p.Arg1740Trp. This variant was reported to be a recurrent de novo variant in more than 10 individuals with Rabin-Pappas syndrome (Rabin et al. 2020. PubMed ID: 32710489). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1740 of the SETD2 protein (p.Arg1740Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SETD2-related conditions (PMID: 31474318, 32710489). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 388568). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SETD2 protein function. For these reasons, this variant has been classified as Pathogenic.

The de novo c.5218C>T (p. Arg1740Trp) missense variant identified in exon 10 (of 21) of the SETD2 gene has been reported as heterozygous de novo in at least 12 individuals affected with SETD2-NDD with MCA [PMID: 32710489; group1 in the article]. A different missense variant (p.Arg1740Gln) affecting the same codon Arg1740 has been reported in 3 individuals (PMID: 32710489; group2 in the article). The c.5218C>T (p. Arg1740Trp) variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. This variant has been reported in the ClinVar database with conflicting interpretations of pathogenicity [likely pathogenic (3), pathogenic (2), and variant of uncertain significance (1). Variation ID: 388568]. The variant affects an evolutionarily conserved residue and is predicted deleterious by multiple in silico prediction tools (CADD score = 27.2 and REVEL score = 0.741). Based on the available evidence, the de novo c.5218C>T (p.Arg1740Trp) variant identified in the SETD2 gene is reported as Pathogenic.

Only variant known to be assoc w/SETD2-NDD w/MCA