NM_001372044.2(SHANK3):c.3989_4001del (p.Arg1330fs) AND Phelan-McDermid syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 17, 2019
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:: RCV001249687.10

Allele description [Variation Report for NM_001372044.2(SHANK3):c.3989_4001del (p.Arg1330fs)]

NM_001372044.2(SHANK3):c.3989_4001del (p.Arg1330fs)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

22q13.33

Genomic location:

Preferred name:

NM_001372044.2(SHANK3):c.3989_4001del (p.Arg1330fs)

Other names:

NM_001080420.1:c.3812_3824del

HGVS:

NC_000022.11:g.50721597_50721609del
NG_070230.1:g.57381_57393del
NM_001372044.2:c.3989_4001delMANE SELECT
NM_033517.1:c.3764_3776del
NP_001358973.1:p.Arg1330fs
NP_277052.1:p.Arg1255Leufs
NP_277052.1:p.Arg1255fs
NC_000022.10:g.51160025_51160037del
NM_033517.1:c.3764_3776del13
NM_033517.1:c.3764_3776delGGGCCCAGCCCCC

Protein change:

R1255fs

Links:

dbSNP: rs886041238

NCBI 1000 Genomes Browser:

rs886041238

Molecular consequence:

NM_001372044.2:c.3989_4001del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_033517.1:c.3764_3776del - 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

Recent activity

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Homo sapiens solute carrier family 2 member 2 (SLC2A2), transcript variant 3, mR...
Homo sapiens solute carrier family 2 member 2 (SLC2A2), transcript variant 3, mRNA
gi|1676317765|ref|NM_001278659.2|

Nucleotide
solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [Ho...
solute carrier family 2, facilitated glucose transporter member 2 isoform X1 [Homo sapiens]
gi|2462592065|ref|XP_054203585.1|

Protein
2,4-D-degrading bacterium 021 16S ribosomal RNA gene, partial sequence
2,4-D-degrading bacterium 021 16S ribosomal RNA gene, partial sequence
gi|10039583|gb|AF176849.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001423683	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 17, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001977612	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego - CSER-NYCKidSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	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

SCV001423683

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 17, 2019)

germline

clinical testing

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

SCV001977612

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego - CSER-NYCKidSeq

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic

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 Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital, SCV001423683.1

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

Description

[ACMG/AMP: PVS1, PS2, PM2] This alteration is a null variant in a gene where LOF is a known mechanism of disease [PVS1], is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is absent from or rarely observed in large-scale population databases [PM2].

#	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

From Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego - CSER-NYCKidSeq, SCV001977612.1

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

Description

This nonsense variant found in exon 21 of 22 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). De novo deletions, of a similar size to the one identified in this individual, have been previously reported in individuals affected with Phelan McDermid syndrome (PMID: 29719671, 25188300, 28135719). It is absent from the gnomAD population database and thus is presumed to be rare. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.3812_3824del (p.Arg1271LeufsTer25) variant is classified as 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		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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