Submissions for variant NM_006662.3(SRCAP):c.7303C>T (p.Arg2435Ter)

dbSNP: rs199469465

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UCLA Clinical Genomics Center, UCLA	RCV000023896	SCV000255476	pathogenic	Floating-Harbor syndrome	2014-05-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000299481	SCV000329537	pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing	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)
Eurofins Ntd Llc (ga)	RCV000299481	SCV000338561	pathogenic	not provided	2015-12-18	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000023896	SCV000746577	pathogenic	Floating-Harbor syndrome	2016-08-15	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000023896	SCV000803799	pathogenic	Floating-Harbor syndrome	2017-07-10	criteria provided, single submitter	clinical testing
Department of Medical Genetics, Oslo University Hospital	RCV000023896	SCV001437579	pathogenic	Floating-Harbor syndrome		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001265998	SCV001444170	pathogenic	Inborn genetic diseases	2023-06-27	criteria provided, single submitter	clinical testing	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.
Invitae	RCV000299481	SCV001579743	pathogenic	not provided	2023-10-22	criteria provided, single submitter	clinical testing	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.
Kariminejad - Najmabadi Pathology & Genetics Center	RCV000299481	SCV001755588	likely pathogenic	not provided	2021-07-10	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000299481	SCV002009546	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000023896	SCV002768142	pathogenic	Floating-Harbor syndrome	2022-02-02	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: 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023896	SCV003928305	pathogenic	Floating-Harbor syndrome	2023-04-27	criteria provided, single submitter	clinical testing	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.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000023896	SCV004014017	pathogenic	Floating-Harbor syndrome	2023-02-24	criteria provided, single submitter	clinical testing	PVS1, PM2, PP5
Illumina Laboratory Services, Illumina	RCV000023896	SCV004014714	pathogenic	Floating-Harbor syndrome	2023-05-02	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000023896	SCV000045187	pathogenic	Floating-Harbor syndrome	2013-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000023896	SCV000055881	not provided	Floating-Harbor syndrome		no assertion provided	literature only
Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Peking Union Medical College Hospital	RCV000023896	SCV001482346	pathogenic	Floating-Harbor syndrome	2019-05-31	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000299481	SCV001740586	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000299481	SCV001932671	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000299481	SCV001959917	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000299481	SCV001967490	pathogenic	not provided		no assertion criteria provided	clinical testing