ClinVar Genomic variation as it relates to human health
NM_033517.1(SHANK3):c.3679dup (p.Ala1227fs)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_033517.1(SHANK3):c.3679dup (p.Ala1227fs)
Variation ID: 208759 Accession: VCV000208759.35
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 22q13.33 22: 50721504-50721505 (GRCh38) [ NCBI UCSC ] 22: 51159932-51159933 (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 Sep 14, 2015 May 12, 2024 Jul 24, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001372044.2:c.3904dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_001372044.1:c.3904dup NM_033517.1:c.3679dup NP_277052.1:p.Ala1227fs frameshift NM_033517.1:c.3679dupG NC_000022.11:g.50721512dup NC_000022.10:g.51159940dup - Protein change
- A1227fs
- Other names
- NM_001080420.1:c.3727dupG
- Canonical SPDI
- NC_000022.11:50721504:GGGGGGGG:GGGGGGGGG
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- functionally_abnormal Sequence Ontology [SO:0002218]
-
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.
-
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. |
|||
SHANK3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
801 | 1026 |
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 (9) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2023 | RCV000004730.25 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jan 26, 2022 | RCV000190779.10 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 14, 2022 | RCV000366708.24 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2018 | RCV000754675.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
Sep 14, 2020 | RCV001374986.8 | |
Pathogenic (1) |
criteria provided, single submitter
|
Feb 1, 2022 | RCV002503748.8 |
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
(Aug 01, 2018)
|
criteria provided, single submitter
Method: research
|
Autism spectrum disorder
Affected status: yes
Allele origin:
unknown,
de novo
|
Liping Wei Laboratory, Peking University
Accession: SCV000804767.2
First in ClinVar: Feb 04, 2019 Last updated: Feb 04, 2019 |
Observation 1:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Chinese
Observation 2:
Number of individuals with the variant: 1
Sex: female
Ethnicity/Population group: Chinese
|
|
Pathogenic
(Jan 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329516.8
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
Comment:
Reported in two male siblings with autism with presumed germline mosaicism in their mother (Durand et al., 2007); Frameshift variant predicted to result in protein … (more)
Reported in two male siblings with autism with presumed germline mosaicism in their mother (Durand et al., 2007); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32050889, 33256793, 21565394, 21606927, 23100419, 25356970, 17173049, 29719671, 30763456, 34737294, 33619735) (less)
|
|
Pathogenic
(Feb 07, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149930.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV001437685.1
First in ClinVar: Oct 20, 2020 Last updated: Oct 20, 2020 |
Comment:
PVS1, PS2, PS3, PP5
Clinical Features:
Global developmental delay (present) , Intellectual disability, moderate (present)
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
Laboratoire de Génétique Moléculaire, CHU Bordeaux
Accession: SCV001468904.1
First in ClinVar: Jan 17, 2021 Last updated: Jan 17, 2021 |
|
|
Pathogenic
(Sep 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Neurodevelopmental disorder
Affected status: yes
Allele origin:
germline
|
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes
Accession: SCV001572274.1
First in ClinVar: Apr 28, 2021 Last updated: Apr 28, 2021 |
|
|
Pathogenic
(Oct 06, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Affected status: yes
Allele origin:
de novo
|
Centogene AG - the Rare Disease Company
Accession: SCV002059291.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
Pathogenic
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002581218.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS2, PS4, BS2
|
Number of individuals with the variant: 1
Sex: female
|
|
Pathogenic
(Aug 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Accession: SCV002757838.1
First in ClinVar: Dec 03, 2022 Last updated: Dec 03, 2022 |
|
|
Pathogenic
(Feb 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Schizophrenia 15
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002801553.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Autism spectrum disorder
Affected status: yes
Allele origin:
unknown
|
Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine
Accession: SCV003804121.1
First in ClinVar: Feb 18, 2023 Last updated: Feb 18, 2023 |
Sex: female
|
|
Pathogenic
(Mar 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV003932193.1
First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023 |
Comment:
PVS1, PS2
|
|
Pathogenic
(Jul 24, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004027637.1
First in ClinVar: Aug 26, 2023 Last updated: Aug 26, 2023 |
Comment:
Criteria applied: PVS1,PS2,PS3,PS4
Clinical Features:
Hypotonia (present) , Global developmental delay (present) , Weight loss (present) , Developmental regression (present)
Sex: female
|
|
Pathogenic
(Sep 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phelan-McDermid syndrome
Affected status: unknown
Allele origin:
unknown
|
Illumina Laboratory Services, Illumina
Accession: SCV004801628.1
First in ClinVar: Mar 23, 2024 Last updated: Mar 23, 2024 |
Comment:
The SHANK3 c.3679dupG p.(Ala1227GlyTer56) variant, also referred to as p.(Ala1214GlyTer69), p.(Ala1227Glyfs), or p.(Ala1243GlyfsTer69), causes a shift in the protein reading frame that is predicted to … (more)
The SHANK3 c.3679dupG p.(Ala1227GlyTer56) variant, also referred to as p.(Ala1214GlyTer69), p.(Ala1227Glyfs), or p.(Ala1243GlyfsTer69), causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been identified in individuals with a phenotype consistent with Phelan-McDermid syndrome (Durand et al. 2007; O'Roak et al. 2014; De Rubeis et al. 2018; Zhou et al. 2019). De novo inheritance was confirmed in four of the cases as well as germline mosaicism in a sibling pair who inherited the variant from the mother. This variant is not observed in version 2.1.1 of the Genome Aggregation Database. The Ala1227 residue lies in exon 21, which has been shown to be a hotspot for de novo variants resulting in loss of function (De Rubeis et al. 2018). The variant was identified in a de novo state in the proband. Based on the collective evidence, the c.3679dupG p.(Ala1227GlyTer56) variant is classified as pathogenic for Phelan-McDermid syndrome. (less)
|
|
Pathogenic
(Jan 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000850848.5
First in ClinVar: Nov 08, 2018 Last updated: May 01, 2024 |
Comment:
The c.3679dupG (p.A1227Gfs*69) alteration, located in exon 21 (coding exon 21) of the SHANK3 gene, consists of a duplication of G at position 3679, causing … (more)
The c.3679dupG (p.A1227Gfs*69) alteration, located in exon 21 (coding exon 21) of the SHANK3 gene, consists of a duplication of G at position 3679, causing a translational frameshift with a predicted alternate stop codon after 69 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This has been reported to be a recurrent mutation in individuals with autism spectrum disorder and Phelan-McDermid syndrome, often occurring de novo (Durand, 2007; De Rubeis, 2018; Loureiro, 2021). Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
Pathogenic
(Apr 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001746451.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Jan 01, 2007)
|
no assertion criteria provided
Method: literature only
|
PHELAN-MCDERMID SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024906.4
First in ClinVar: Apr 04, 2013 Last updated: Jan 10, 2020 |
Comment on evidence:
In 2 brothers with severely impaired speech, severe mental retardation, and autistic features consistent with Phelan-McDermid syndrome (PHMDS; 606232), Durand et al. (2007) identified a … (more)
In 2 brothers with severely impaired speech, severe mental retardation, and autistic features consistent with Phelan-McDermid syndrome (PHMDS; 606232), Durand et al. (2007) identified a heterozygous 1-bp insertion (3680insG) in exon 21 of the SHANK3 gene, resulting in a frameshift and premature termination of the protein lacking several crucial domains involved in synaptic targeting and postsynaptic assembly of SHANK3 multimers. Consistent with the loss of these domains, Durand et al. (2007) observed no synaptic localization following overexpression of the truncated protein in rat hippocampal neuronal cells compared with the wildtype sequence. (less)
|
|
click to load more click to collapse |
Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
---|---|---|---|---|
functionally_abnormal
|
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV001437685.1
|
|
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
A recurrent SHANK3 frameshift variant in Autism Spectrum Disorder. | Loureiro LO | NPJ genomic medicine | 2021 | PMID: 34737294 |
Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. | Zhou WZ | Human mutation | 2019 | PMID: 30763456 |
Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. | De Rubeis S | Molecular autism | 2018 | PMID: 29719671 |
Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. | Durand CM | Nature genetics | 2007 | PMID: 17173049 |
Text-mined citations for rs762292772 ...
HelpRecord last updated Jun 10, 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.