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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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV001423683Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Jan 17, 2019) 		germlineclinical testing

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

SCV001977612Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego - CSER-NYCKidSeq
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenicgermlineclinical testing

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

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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].

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024