NM_001372044.2(SHANK3):c.4613dup (p.Arg1539fs) AND Phelan-McDermid syndrome

Germline classification:: Uncertain significance (1 submission)
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003337931.2

Allele description [Variation Report for NM_001372044.2(SHANK3):c.4613dup (p.Arg1539fs)]

NM_001372044.2(SHANK3):c.4613dup (p.Arg1539fs)

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.4613dup (p.Arg1539fs)

HGVS:

NC_000022.11:g.50722221dup
NG_070230.1:g.58005dup
NM_001372044.2:c.4613dupMANE SELECT
NM_033517.1:c.4388dup
NP_001358973.1:p.Arg1539fs
NP_277052.1:p.Arg1464Serfs
NC_000022.10:g.51160649dup
NM_001372044.1:c.4612dup

Protein change:

R1539fs

Molecular consequence:

NM_001372044.2:c.4613dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033517.1:c.4388dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV004048370	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004048370

Neuberg Centre For Genomic Medicine, NCGM

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	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

Details of each submission

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048370.1

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

Description

The frameshift SHANK3 (p.Asp1538GlyfsTer12) variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Asp1538GlyfsTer12 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant causes a frameshift starting with codon Aspartic Acid 1538, changes this amino acid to Glycine residue, and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Asp1538GlyfsTer12. However since this variant is present in the penultimate exon functional studies will be required to prove protein truncation. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).

#	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		not provided	not provided	not provided	not provided

Last Updated: Apr 6, 2024

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