NM_001372044.2(SHANK3):c.3865dup (p.Ala1289fs) AND Phelan-McDermid syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Nov 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001813907.5

Allele description [Variation Report for NM_001372044.2(SHANK3):c.3865dup (p.Ala1289fs)]

NM_001372044.2(SHANK3):c.3865dup (p.Ala1289fs)

Gene:

SHANK3:SH3 and multiple ankyrin repeat domains 3 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_001372044.2(SHANK3):c.3865dup (p.Ala1289fs)

HGVS:

NC_000022.11:g.50721473dup
NG_070230.1:g.57257dup
NM_001372044.2:c.3865dupMANE SELECT
NP_001358973.1:p.Ala1289fs
NC_000022.10:g.51159901dup
NM_001372044.1:c.3865dup

Protein change:

A1289fs

Links:

dbSNP: rs2146831793

NCBI 1000 Genomes Browser:

rs2146831793

Molecular consequence:

NM_001372044.2:c.3865dup - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Phelan-McDermid syndrome
Synonyms:: TELOMERIC 22q13 MONOSOMY SYNDROME; 22q13.3 deletion syndrome; Chromosome 22q13.3 deletion syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011652; MedGen: C1853490; Orphanet: 48652; OMIM: 606232

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002061232	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 30763456, 29719671, 25356970, 17173049, 25741868
SCV002572730	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847182	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 12, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25741868, 30763456, 29719671, 25356970, 17173049

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002061232

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002572730

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 1, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004847182

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 12, 2023)

unknown

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations.

Zhou WZ, Zhang J, Li Z, Lin X, Li J, Wang S, Yang C, Wu Q, Ye AY, Wang M, Wang D, Pu TZ, Wu YY, Wei L.

Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.

PubMed [citation]

PMID:: 30763456
PMCID:: PMC6593842

See all PubMed Citations (5)

Details of each submission

From DASA, SCV002061232.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

Description

The c.3865dup;p.(Ala1289Glyfs*69) is a null frameshift variant (NMD) in the SHANK3 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 208759; PMID: 30763456; 29719671; 25356970; 17173049) - PS4. This variant is not present in population databases (rs762292772, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From 3billion, SCV002572730.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. However, the variant is of a low quality and therefore the allele frequency information is unreliable. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000208759). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Equipe Genetique des Anomalies du Developpement, Université de Bourgogne, SCV004847182.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	discovery		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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