ClinVar Genomic variation as it relates to human health

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is the likely mechanism of disease in this gene relating to the cluster of pathogenic protein truncating variants in SRCAP exons 33 and 34 and associated Floating-Harbor syndrome (MIM#136140) (PMID: 22265015, GeneReviews) while the disease mechanism associated with missense variants is currently unclear. It should also be noted that haploinsufficiency has been suggested for pathogenic variants associated with the newly described ‘non-Floating-Harbor syndrome SRCAP-related neurodevelopmental disorder’ (PMID: 33909990). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants associated with Floating-Harbor syndrome (GeneReviews). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been described as a recurrent pathogenic variant in individuals with Floating-Harbor syndrome (ClinVar, PMIDs: 31200758, 33909990). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

PVS1, PM2, PP5

This sequence change creates a premature translational stop signal (p.Arg2435*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 796 amino acid(s) of the SRCAP protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 22965468, 23621943, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30909). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 796 amino acids are lost, 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: 23165645, 22265015, 25433523, 26788936, 22965468, 20358590, 31200758, 31248274, 31607746, 31605816, 32170002, 34006472)

Variant summary: SRCAP c.7303C>T (p.Arg2435X) results in a premature termination codon which is not expected to undergo nonsense mediated decay, however does disrupt the last 796 amino acids of the protein. The variant was absent in 249920 control chromosomes. c.7303C>T has been reported in the literature in individuals affected with Floating-Harbor Syndrome, including cases where de novo inheritance was confirmed (Hood_2012, Lee_2014, Tonne_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22265015, 25326637, 33288889). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The SRCAP c.7303C>T (p.Arg2435Ter) nonsense variant occurs in the last exon of the gene and may escape nonsense-mediated mRNA decay, although multiple downstream truncating variants are considered causative in the literature (PMID: 35664296). This variant has been identified in multiple individuals with a phenotype consistent with Floating-Harbor syndrome and was confirmed as de novo in several individuals (PMID: 23621943; 22265015; 34006472). The c.7303C>T variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by multiple submitters in ClinVar. The c.7303C>T variant was identified in a de novo state. Based on the available evidence, the c.7303C>T (p.Arg2435Ter) variant is classified as pathogenic for Floating-Harbor syndrome.

The c.7303C>T (p.R2435*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7303. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2435. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 24.6% of the protein. However, premature stop codons are typically deleterious in nature, a significant portion of the protein is affected, and the impacted region is critical for protein function (Ambry internal data)._x000D_ _x000D_ This variant is expected to be causative of Floating-Harbor syndrome; however, its clinical significance for SRCAP-related neurodevelopmental disorder is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration was reported in multiple individuals with features consistent with Floating-Harbor syndrome, including multiple cases of reported de novo occurrence (Hood, 2012; Reschen, 2012; Le Goff, 2013; Nikkel, 2013; Seifert, 2014; Yagi, 2016; Homma, 2019; Zhang, 2019; Lee, 2020; Squeo, 2020). This alteration demonstrated a DNA methylation episignature consistent with Floating-Harbor Syndrome on a genome-wide DNA methylation assay (Kerkhof, 2022). Based on the available evidence, this alteration is classified as pathogenic.