Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000587685.9, PMID: 29961569, 32399599, 32376980, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_032271.3(TRAF7):c.1964G>A (p.Arg655Gln)
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.
(12)
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.
Conflicting classifications of pathogenicity
Pathogenic(8); Likely pathogenic(2); Uncertain significance(1)
Pathogenic(8); Likely pathogenic(2); Uncertain significance(1)
12
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_032271.3(TRAF7):c.1964G>A (p.Arg655Gln)
Variation ID: 587685 Accession: VCV000587685.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16p13.3 16: 2176350 (GRCh38) [ NCBI UCSC ] 16: 2226351 (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 Nov 5, 2018 Jun 9, 2024 Feb 21, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_032271.3:c.1964G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_115647.2:p.Arg655Gln missense NC_000016.10:g.2176350G>A NC_000016.9:g.2226351G>A - Protein change
- R655Q
- Other names
-
p.Arg655Gln
- Canonical SPDI
- NC_000016.10:2176349:G:A
-
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. |
|||
| TRAF7 | - | - |
GRCh38 GRCh37 |
143 | 193 | |
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. |
|---|---|---|---|---|
| Conflicting interpretations of pathogenicity (7) |
criteria provided, conflicting classifications
|
Feb 21, 2024 | RCV000714967.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 3, 2018 | RCV001266877.2 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 29, 2023 | RCV001571649.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV002274096.2 | |
|
TRAF7-related syndrome
|
Pathogenic (1) |
criteria provided, single submitter
|
Mar 17, 2022 | RCV002466575.3 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139799.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
|
Likely pathogenic
(May 10, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Genomic Medicine Lab, University of California San Francisco
Study: CSER
Accession: SCV001167584.1 First in ClinVar: Mar 14, 2020 Last updated: Mar 14, 2020 |
Sex: female
Secondary finding: no
|
|
|
Uncertain significance
(Mar 22, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001429309.1
First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Oct 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002012331.1
First in ClinVar: Nov 11, 2021 Last updated: Nov 11, 2021 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated … (more)
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000587685.9, PMID: 29961569, 32399599, 32376980, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Delayed gross motor development (present) , Prominent forehead (present) , Intellectual disability (present) , Abnormal eyelid morphology (present) , Hypertelorism (present) , Micrognathia (present) , … (more)
Delayed gross motor development (present) , Prominent forehead (present) , Intellectual disability (present) , Abnormal eyelid morphology (present) , Hypertelorism (present) , Micrognathia (present) , Blepharophimosis (present) , Specific learning disability (present) , Growth delay (present) , Short stature (present) , Bicuspid aortic valve (present) , Specific learning disability (present) , Flexion contracture (present) , Delayed fine motor development (present) , Delayed fine motor development (present) , Abnormal eyelid morphology (present) , Hearing impairment (present) (less)
|
|
|
Pathogenic
(Apr 14, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Undiagnosed Diseases Network, NIH
Study: Undiagnosed Diseases Network (NIH), UDN
Accession: SCV000863425.3 First in ClinVar: Dec 16, 2018 Last updated: Dec 12, 2021 |
Observation 1:
Age: 40-49 years
Sex: male
Tissue: blood
Comment on evidence:
This individual has been published in PMID: 29961569.
Observation 2:
Age: 10-19 years
Sex: female
Tissue: blood
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndrome
Affected status: yes
Allele origin:
unknown
|
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille
Accession: SCV002558900.1
First in ClinVar: Aug 15, 2022 Last updated: Aug 15, 2022 |
|
|
|
Pathogenic
(Mar 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
TRAF7-related syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV002762682.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The TRAF7 c.1964G>A (p.Arg655Gln) missense variant results in the substitution of arginine at amino acid position 655 with glutamine. The c.1964G>A variant is a recurrent … (more)
The TRAF7 c.1964G>A (p.Arg655Gln) missense variant results in the substitution of arginine at amino acid position 655 with glutamine. The c.1964G>A variant is a recurrent missense variant that has been reported in a heterozygous state in over 15 affected individuals in three studies. In most cases, the variant was confirmed to be de novo in origin (Tokita et al. 2018; Accogli et al. 2020; Castilla-Vallmanya et al. 2020). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The Arg655 residue is located in the seventh WD40 domain and is highly conserved through evolution. In vitro functional expression assays showed that this variant results in decreased MAPK1/MAPK3 phosphorylation after TNF-alpha stimulation compared to controls (Tokita et al. 2018). Transcriptomic studies of patient fibroblasts also revealed several differentially expressed genes after TNF-alpha treatment compared to controls (Castilla-Vallmanya et al. 2020). Based on the available evidence, the c.1964G>A (p.Arg655Gln) variant is classified as pathogenic for TRAF7-related syndrome. (less)
|
|
|
Pathogenic
(Jul 03, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001445057.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Bilateral ptosis (present) , Aqueductal stenosis (present) , Sacral dimple (present) , Flat occiput (present) , Inguinal hernia (present) , Telecanthus (present) , Long philtrum … (more)
Bilateral ptosis (present) , Aqueductal stenosis (present) , Sacral dimple (present) , Flat occiput (present) , Inguinal hernia (present) , Telecanthus (present) , Long philtrum (present) , Clinodactyly (present) , Short neck (present) , Frontal bossing (present) , Hydrocephalus (present) , Blepharophimosis (present) , Anteverted nares (present) , Hypertelorism (present) , Strabismus (present) , Short stature (present) , Intellectual disability, mild (present) , Narrow mouth (present) , Protruding ear (present) , Ventriculomegaly (present) , Mixed hearing impairment (present) , Short digit (present) (less)
Sex: male
Ethnicity/Population group: Caucasian
|
|
|
Pathogenic
(Jun 29, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001796158.2
First in ClinVar: Aug 21, 2021 Last updated: Jul 08, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32459067, 31036916, 29961569, 25961944, 32376980, 28714951, 31981491, 32399599) (less)
|
|
|
Pathogenic
(May 10, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003461737.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 655 of the TRAF7 protein (p.Arg655Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 655 of the TRAF7 protein (p.Arg655Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TRAF7-related conditions (PMID: 29961569). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 587685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TRAF7 function (PMID: 29961569). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Feb 21, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiac, facial, and digital anomalies with developmental delay
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV003835217.2
First in ClinVar: Mar 11, 2023 Last updated: Jun 09, 2024 |
|
|
|
Pathogenic
(Oct 31, 2018)
|
no assertion criteria provided
Method: literature only
|
CARDIAC, FACIAL, AND DIGITAL ANOMALIES WITH DEVELOPMENTAL DELAY
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000845732.1
First in ClinVar: Nov 05, 2018 Last updated: Nov 05, 2018 |
Comment on evidence:
In 4 unrelated patients (subjects 1 through 4) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a … (more)
In 4 unrelated patients (subjects 1 through 4) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a de novo heterozygous c.1964G-A transition (c.1964G-A, NM_032271.2) in exon 20 of the TRAF7 gene, resulting in an arg655-to-gln (R655Q) substitution at a conserved reside in the seventh WD40 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Tokita et al. (2018) noted that Krumm et al. (2015) had identified a de novo heterozygous R655Q mutation in the TRAF7 gene in a patient with autism who was part of a cohort of 2,377 families with autism. (less)
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Comment:
Comment:
The TRAF7 c.1964G>A (p.Arg655Gln) missense variant results in the substitution of arginine at amino acid position 655 with glutamine. The c.1964G>A variant is a recurrent missense variant that has been reported in a heterozygous state in over 15 affected individuals in three studies. In most cases, the variant was confirmed to be de novo in origin (Tokita et al. 2018; Accogli et al. 2020; Castilla-Vallmanya et al. 2020). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The Arg655 residue is located in the seventh WD40 domain and is highly conserved through evolution. In vitro functional expression assays showed that this variant results in decreased MAPK1/MAPK3 phosphorylation after TNF-alpha stimulation compared to controls (Tokita et al. 2018). Transcriptomic studies of patient fibroblasts also revealed several differentially expressed genes after TNF-alpha treatment compared to controls (Castilla-Vallmanya et al. 2020). Based on the available evidence, the c.1964G>A (p.Arg655Gln) variant is classified as pathogenic for TRAF7-related syndrome.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32459067, 31036916, 29961569, 25961944, 32376980, 28714951, 31981491, 32399599)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 655 of the TRAF7 protein (p.Arg655Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TRAF7-related conditions (PMID: 29961569). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 587685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TRAF7 function (PMID: 29961569). For these reasons, this variant has been classified 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:
Same nucleotide change resulting in same amino acid change has been previously reported as de novoo and observed in at least four similarly affected unrelated individuals (ClinVar ID: VCV000587685.9, PMID: 29961569, 32399599, 32376980, PS2 and PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TRAF7 c.1964G>A (p.Arg655Gln) missense variant results in the substitution of arginine at amino acid position 655 with glutamine. The c.1964G>A variant is a recurrent missense variant that has been reported in a heterozygous state in over 15 affected individuals in three studies. In most cases, the variant was confirmed to be de novo in origin (Tokita et al. 2018; Accogli et al. 2020; Castilla-Vallmanya et al. 2020). This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The Arg655 residue is located in the seventh WD40 domain and is highly conserved through evolution. In vitro functional expression assays showed that this variant results in decreased MAPK1/MAPK3 phosphorylation after TNF-alpha stimulation compared to controls (Tokita et al. 2018). Transcriptomic studies of patient fibroblasts also revealed several differentially expressed genes after TNF-alpha treatment compared to controls (Castilla-Vallmanya et al. 2020). Based on the available evidence, the c.1964G>A (p.Arg655Gln) variant is classified as pathogenic for TRAF7-related syndrome.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32459067, 31036916, 29961569, 25961944, 32376980, 28714951, 31981491, 32399599)
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 655 of the TRAF7 protein (p.Arg655Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with TRAF7-related conditions (PMID: 29961569). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 587685). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects TRAF7 function (PMID: 29961569). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Sinus pericranii, skull defects, and structural brain anomalies in TRAF7-related disorder. | Accogli A | Birth defects research | 2020 | PMID: 32459067 |
| Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders. | Tran Mau-Them F | Human genetics | 2020 | PMID: 32399599 |
| Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7. | Castilla-Vallmanya L | Genetics in medicine : official journal of the American College of Medical Genetics | 2020 | PMID: 32376980 |
| De Novo Missense Variants in TRAF7 Cause Developmental Delay, Congenital Anomalies, and Dysmorphic Features. | Tokita MJ | American journal of human genetics | 2018 | PMID: 29961569 |
| Excess of rare, inherited truncating mutations in autism. | Krumm N | Nature genetics | 2015 | PMID: 25961944 |
Text-mined citations for rs1331463984 ...
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 Sep 29, 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.