The SRCAP c.7330C>T (p.Arg2444Ter) variant is a stop-gained variant that is the most frequently reported recurrent variant associated with Floating-Harbor syndrome (Nowaczyk et al. 2012). It has been identified in a heterozygous state in at least 24 unrelated individuals and was confirmed to have occurred de novo in at least three (Hood et al. 2012; Nikkel et al. 2013). The p.Arg2444Ter variant is not reported in the Genome Aggregation Databasea in a region of good sequencing coverage. This variant is predicted to result in premature truncation of the SRCAP protein, including loss of the three C-terminal AT-hook motifs involved in DNA binding, and is expected to inhibit CREB-mediated transactivation via a dominant-negative mechanism (Monroy et al. 2001). Based on the collective evidence, the p.Arg2444Ter variant is classified as pathogenic for Floating-Harbor syndrome.
ClinVar Genomic variation as it relates to human health
NM_006662.3(SRCAP):c.7330C>T (p.Arg2444Ter)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(27)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic
27
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_006662.3(SRCAP):c.7330C>T (p.Arg2444Ter)
Variation ID: 30908 Accession: VCV000030908.74
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p11.2 16: 30737370 (GRCh38) [ NCBI UCSC ] 16: 30748691 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Oct 20, 2024 May 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_006662.3:c.7330C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006653.2:p.Arg2444Ter nonsense NC_000016.10:g.30737370C>T NC_000016.9:g.30748691C>T NG_032135.1:g.43230C>T - Protein change
- R2444*
- Other names
-
p.Arg2444Ter
- Canonical SPDI
- NC_000016.10:30737369:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| SRCAP | Little evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1527 | 1549 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Sep 28, 2022 | RCV000023895.34 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000255081.46 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 16, 2022 | RCV000623916.6 | |
|
See cases
|
Pathogenic (1) |
criteria provided, single submitter
|
Apr 26, 2021 | RCV001420319.4 |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002273937.3 | |
|
SRCAP-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Sep 17, 2024 | RCV003407357.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 22, 2024 | RCV003988823.1 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental delay
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002559085.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Nov 15, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV001423753.2
First in ClinVar: Jul 25, 2020 Last updated: Mar 04, 2023 |
Comment:
The SRCAP c.7330C>T (p.Arg2444Ter) variant is a stop-gained variant that is the most frequently reported recurrent variant associated with Floating-Harbor syndrome (Nowaczyk et al. 2012). … (more)
The SRCAP c.7330C>T (p.Arg2444Ter) variant is a stop-gained variant that is the most frequently reported recurrent variant associated with Floating-Harbor syndrome (Nowaczyk et al. 2012). It has been identified in a heterozygous state in at least 24 unrelated individuals and was confirmed to have occurred de novo in at least three (Hood et al. 2012; Nikkel et al. 2013). The p.Arg2444Ter variant is not reported in the Genome Aggregation Databasea in a region of good sequencing coverage. This variant is predicted to result in premature truncation of the SRCAP protein, including loss of the three C-terminal AT-hook motifs involved in DNA binding, and is expected to inhibit CREB-mediated transactivation via a dominant-negative mechanism (Monroy et al. 2001). Based on the collective evidence, the p.Arg2444Ter variant is classified as pathogenic for Floating-Harbor syndrome. (less)
|
|
|
Pathogenic
(Apr 29, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000195117.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
|
|
|
Pathogenic
(Feb 09, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000339642.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: unknown
Allele origin:
unknown
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV002576366.1 First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
|
|
|
Pathogenic
(Feb 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322046.9
First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 787 amino acids are lost, and other loss-of-function variants have been … (more)
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 787 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: 25590979, 23621943, 27815143, 31874661, 27206688, 24970356, 25433523, 22965468, 22265015, 27515243, 30425916, 31200758, 31630891, 27899421, 31715605, 33776628, 32939031, 33726816) (less)
|
|
|
Pathogenic
(Sep 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
de novo
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV004013952.1
First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023 |
Comment:
PVS1, PS2, PM2, PP5
|
|
|
Pathogenic
(Mar 31, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002021960.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Aug 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001581340.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2444*) in the SRCAP gene. … (more)
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2444*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 787 amino acid(s) of the SRCAP protein. This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 23621943, 24970356, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30908). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(May 27, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198353.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894077.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Dec 10, 2018)
|
criteria provided, single submitter
Method: research
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
de novo
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: HudsonAlpha-AGHI-WGS
Accession: SCV000993598.1 First in ClinVar: Sep 25, 2019 Last updated: Sep 25, 2019 |
Number of individuals with the variant: 1
Clinical Features:
Oral cleft (present) , Abnormal hair pattern (present) , Hypotelorism (present) , Macrotia (present) , Convex nasal ridge (present) , Narrow mouth (present)
|
|
|
Pathogenic
(Apr 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
See cases
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Genetics Laboratory, UDIAT-Centre Diagnòstic, Hospital Universitari Parc Tauli
Accession: SCV001622739.1
First in ClinVar: May 20, 2021 Last updated: May 20, 2021 |
Comment:
PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate;PP3_supporting
Clinical Features:
Global developmental delay (present) , Cleft lip (present) , Motor delay (present) , Delayed speech and language development (present) , Microcephaly (present) , Abnormal facial … (more)
Global developmental delay (present) , Cleft lip (present) , Motor delay (present) , Delayed speech and language development (present) , Microcephaly (present) , Abnormal facial shape (present) , Short stature (present) , Hypoplasia of the corpus callosum (present) (less)
Sex: female
|
|
|
Pathogenic
(Feb 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512494.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PVS1 strong, PS4 moderate, PM1, PM2, PM6
Geographic origin: Brazil
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521421.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030908 / PMID: 22265015 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Severe short stature (present) , Thin vermilion border (present) , Precocious puberty (present) , Prominent nose (present) , Long eyelashes (present) , Expressive language delay … (more)
Severe short stature (present) , Thin vermilion border (present) , Precocious puberty (present) , Prominent nose (present) , Long eyelashes (present) , Expressive language delay (present) , Delayed skeletal maturation (present) , Fetal growth restriction (present) (less)
|
|
|
Pathogenic
(May 13, 2022)
|
criteria provided, single submitter
Method: research
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
de novo
|
Laboratory of Human Genetics, Universidade de São Paulo
Accession: SCV002522322.1
First in ClinVar: Jul 22, 2022 Last updated: Jul 22, 2022 |
Comment:
This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity.
Clinical Features:
Microcephaly (present)
Sex: male
|
|
|
Pathogenic
(Mar 22, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV004805230.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
A heterozygous nonsense variant in exon 34 of the SRCAP gene that results in a stop codon and premature truncation of the protein at codon … (more)
A heterozygous nonsense variant in exon 34 of the SRCAP gene that results in a stop codon and premature truncation of the protein at codon 2444 (p.Arg2444Ter) was detected. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. (less)
Age: 0-9 years
Sex: male
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on the Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
|
|
|
Pathogenic
(Aug 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000742449.5
First in ClinVar: Apr 15, 2018 Last updated: May 01, 2024 |
Comment:
The c.7330C>T (p.R2444*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position … (more)
The c.7330C>T (p.R2444*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7330. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2444. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 24% of the protein. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.7330C>T, p.R2444* alteration has been previously reported in multiple unrelated patients with Floating-Harbor syndrome (Hood, 2012; Guo, 2014; Seifert, 2014; Zhu, 2015). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 21, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Floating-Harbor syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV001427115.4
First in ClinVar: Aug 13, 2020 Last updated: Jul 23, 2024 |
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease … (more)
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 34 of 34). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Hood, RL. et al. (2012), Zhang, S. et al. (2019)). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign (less)
|
|
|
Pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248454.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
SRCAP: PS2:Very Strong, PVS1:Strong, PM2
Number of individuals with the variant: 6
|
|
|
Pathogenic
(Jan 01, 2013)
|
no assertion criteria provided
Method: literature only
|
FLOATING-HARBOR SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000045186.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 21, 2017 |
Comment on evidence:
In 6 unrelated patients with Floating-Harbor syndrome (FLHS; 136140), 2 of whom were previously studied by White et al. (2010) (patients 9 and 10), Hood … (more)
In 6 unrelated patients with Floating-Harbor syndrome (FLHS; 136140), 2 of whom were previously studied by White et al. (2010) (patients 9 and 10), Hood et al. (2012) identified heterozygosity for a 7330C-T transition in exon 34 of the SRCAP gene, resulting in an arg2444-to-ter (R2444X) substitution. The mutation was shown to be de novo in the 2 patients for whom parental DNA was available, and was not represented in the dbSNP (build 131), 1000 Genomes Project, or NHLBI Exome Variant Server databases. In a 32-year-old French woman and a 28-year-old woman of Spanish and Portuguese ancestry with Floating-Harbor syndrome, Le Goff et al. (2013) identified heterozygosity for the R2444X mutation in the SRCAP gene. The mutation occurred de novo in both women and was not found in 200 control chromosomes. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001928898.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001956647.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Floating-Harbor syndrome
Affected status: yes
Allele origin:
de novo
|
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
Accession: SCV002553184.1
First in ClinVar: Jul 28, 2022 Last updated: Jul 28, 2022 |
|
|
|
Pathogenic
(Sep 17, 2024)
|
no assertion criteria provided
Method: clinical testing
|
SRCAP-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004115975.2
First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024 |
Comment:
The SRCAP c.7330C>T variant is predicted to result in premature protein termination (p.Arg2444*). This variant was reported to be one of two recurrent pathogenic variants … (more)
The SRCAP c.7330C>T variant is predicted to result in premature protein termination (p.Arg2444*). This variant was reported to be one of two recurrent pathogenic variants for Floating-Harbor Syndrome (Nikkel et al. 2013. PubMed ID: 23621943; Goff et al. 2013. PubMed ID: 22965468). We have also observed this variant previously at PreventionGenetics in several other affected individuals. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001807387.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Floating-Harbor syndrome
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000055882.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 787 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: 25590979, 23621943, 27815143, 31874661, 27206688, 24970356, 25433523, 22965468, 22265015, 27515243, 30425916, 31200758, 31630891, 27899421, 31715605, 33776628, 32939031, 33726816)
Comment:
PVS1, PS2, PM2, PP5
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2444*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 787 amino acid(s) of the SRCAP protein. This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 23621943, 24970356, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30908). For these reasons, this variant has been classified as Pathogenic.
Comment:
PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate;PP3_supporting
Comment:
ACMG classification criteria: PVS1 strong, PS4 moderate, PM1, PM2, PM6
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030908 / PMID: 22265015 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity.
Comment:
A heterozygous nonsense variant in exon 34 of the SRCAP gene that results in a stop codon and premature truncation of the protein at codon 2444 (p.Arg2444Ter) was detected. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
The c.7330C>T (p.R2444*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7330. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2444. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 24% of the protein. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.7330C>T, p.R2444* alteration has been previously reported in multiple unrelated patients with Floating-Harbor syndrome (Hood, 2012; Guo, 2014; Seifert, 2014; Zhu, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 34 of 34). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Hood, RL. et al. (2012), Zhang, S. et al. (2019)). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
SRCAP: PS2:Very Strong, PVS1:Strong, PM2
Comment:
The SRCAP c.7330C>T variant is predicted to result in premature protein termination (p.Arg2444*). This variant was reported to be one of two recurrent pathogenic variants for Floating-Harbor Syndrome (Nikkel et al. 2013. PubMed ID: 23621943; Goff et al. 2013. PubMed ID: 22965468). We have also observed this variant previously at PreventionGenetics in several other affected individuals. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The SRCAP c.7330C>T (p.Arg2444Ter) variant is a stop-gained variant that is the most frequently reported recurrent variant associated with Floating-Harbor syndrome (Nowaczyk et al. 2012). It has been identified in a heterozygous state in at least 24 unrelated individuals and was confirmed to have occurred de novo in at least three (Hood et al. 2012; Nikkel et al. 2013). The p.Arg2444Ter variant is not reported in the Genome Aggregation Databasea in a region of good sequencing coverage. This variant is predicted to result in premature truncation of the SRCAP protein, including loss of the three C-terminal AT-hook motifs involved in DNA binding, and is expected to inhibit CREB-mediated transactivation via a dominant-negative mechanism (Monroy et al. 2001). Based on the collective evidence, the p.Arg2444Ter variant is classified as pathogenic for Floating-Harbor syndrome.
Comment:
Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 787 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: 25590979, 23621943, 27815143, 31874661, 27206688, 24970356, 25433523, 22965468, 22265015, 27515243, 30425916, 31200758, 31630891, 27899421, 31715605, 33776628, 32939031, 33726816)
Comment:
PVS1, PS2, PM2, PP5
Comment:
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg2444*) in the SRCAP gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 787 amino acid(s) of the SRCAP protein. This premature translational stop signal has been observed in individual(s) with Floating-Harbor syndrome (PMID: 22265015, 23621943, 24970356, 25433523). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30908). For these reasons, this variant has been classified as Pathogenic.
Comment:
PVS1_strong;PP5_very strong;PM2_supporting;PM6_moderate;PP3_supporting
Comment:
ACMG classification criteria: PVS1 strong, PS4 moderate, PM1, PM2, PM6
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000030908 / PMID: 22265015 / 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant meets our criteria to be classified as pathogenic based upon segregation studies, absence from controls, and in-silico evaluation of pathogenicity.
Comment:
A heterozygous nonsense variant in exon 34 of the SRCAP gene that results in a stop codon and premature truncation of the protein at codon 2444 (p.Arg2444Ter) was detected. The variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in-silico prediction of the variant is damaging by MutationTster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.
Comment:
The c.7330C>T (p.R2444*) alteration, located in exon 34 (coding exon 32) of the SRCAP gene, consists of a C to T substitution at nucleotide position 7330. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 2444. This alteration occurs at the 3' terminus of the SRCAP gene, is not expected to trigger nonsense-mediated mRNA decay and only impacts the last 24% of the protein. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). The c.7330C>T, p.R2444* alteration has been previously reported in multiple unrelated patients with Floating-Harbor syndrome (Hood, 2012; Guo, 2014; Seifert, 2014; Zhu, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Comment:
Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0205 - Variant is predicted to result in a truncated protein with less than 1/3 of the protein affected (exon 34 of 34). (P) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0401 - Variant is located in a gene associated with a severe early-onset dominant condition that is intolerant to loss-of-function variants. (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals (ClinVar, Hood, RL. et al. (2012), Zhang, S. et al. (2019)). (P) 1102 - Strong phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Comment:
SRCAP: PS2:Very Strong, PVS1:Strong, PM2
Comment:
The SRCAP c.7330C>T variant is predicted to result in premature protein termination (p.Arg2444*). This variant was reported to be one of two recurrent pathogenic variants for Floating-Harbor Syndrome (Nikkel et al. 2013. PubMed ID: 23621943; Goff et al. 2013. PubMed ID: 22965468). We have also observed this variant previously at PreventionGenetics in several other affected individuals. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Floating-Harbor Syndrome. | Adam MP | - | 2022 | PMID: 23193612 |
| Novel genotypes and phenotypes among Chinese patients with Floating-Harbor syndrome. | Zhang S | Orphanet journal of rare diseases | 2019 | PMID: 31200758 |
| Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. | Zhu X | Genetics in medicine : official journal of the American College of Medical Genetics | 2015 | PMID: 25590979 |
| Expanded spectrum of exon 33 and 34 mutations in SRCAP and follow-up in patients with Floating-Harbor syndrome. | Seifert W | BMC medical genetics | 2014 | PMID: 25433523 |
| Whole exome sequencing to identify genetic causes of short stature. | Guo MH | Hormone research in paediatrics | 2014 | PMID: 24970356 |
| The phenotype of Floating-Harbor syndrome: clinical characterization of 52 individuals with mutations in exon 34 of SRCAP. | Nikkel SM | Orphanet journal of rare diseases | 2013 | PMID: 23621943 |
| Not all floating-harbor syndrome cases are due to mutations in exon 34 of SRCAP. | Le Goff C | Human mutation | 2013 | PMID: 22965468 |
| Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. | Hood RL | American journal of human genetics | 2012 | DOI: 10.1016/j.ajhg.2011.12.001 |
| Mutations in SRCAP, encoding SNF2-related CREBBP activator protein, cause Floating-Harbor syndrome. | Hood RL | American journal of human genetics | 2012 | PMID: 22265015 |
| The phenotype of Floating-Harbor syndrome in 10 patients. | White SM | American journal of medical genetics. Part A | 2010 | PMID: 20358590 |
| Regulation of cAMP-responsive element-binding protein-mediated transcription by the SNF2/SWI-related protein, SRCAP. | Monroy MA | The Journal of biological chemistry | 2001 | PMID: 11522779 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SRCAP | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs199469464 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.