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NM_033056.4(PCDH15):c.4462_4469dup (p.Glu1491fs) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jun 20, 2024
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:
RCV000498908.10

Allele description [Variation Report for NM_033056.4(PCDH15):c.4462_4469dup (p.Glu1491fs)]

NM_033056.4(PCDH15):c.4462_4469dup (p.Glu1491fs)

Gene:
PCDH15:protocadherin related 15 [Gene - OMIM - HGNC]
Variant type:
Duplication
Cytogenetic location:
10q21.1
Genomic location:
Preferred name:
NM_033056.4(PCDH15):c.4462_4469dup (p.Glu1491fs)
HGVS:
  • NC_000010.11:g.53823257_53823264dup
  • NG_009191.3:g.1810919_1810926dup
  • NM_001142763.2:c.4483_4490dup
  • NM_001142764.2:c.4468_4475dup
  • NM_001142765.2:c.4255_4262dup
  • NM_001142766.2:c.4453_4460dup
  • NM_001142767.2:c.4342_4349dup
  • NM_001142768.2:c.4402_4409dup
  • NM_001142769.3:c.4409+1872_4409+1879dup
  • NM_001142770.3:c.4373+1872_4373+1879dup
  • NM_001142771.2:c.4388+1872_4388+1879dup
  • NM_001142772.2:c.4373+1872_4373+1879dup
  • NM_001142773.2:c.4393_4400dup
  • NM_001354404.2:c.4396_4403dup
  • NM_001354411.2:c.4388+4129_4388+4136dup
  • NM_001354420.2:c.4367+4129_4367+4136dup
  • NM_001354429.2:c.4367+4129_4367+4136dup
  • NM_001384140.1:c.4368-3034_4368-3027dupMANE SELECT
  • NM_033056.4:c.4462_4469dup
  • NP_001136235.1:p.Glu1498fs
  • NP_001136236.1:p.Glu1493fs
  • NP_001136237.1:p.Glu1422fs
  • NP_001136238.1:p.Glu1488fs
  • NP_001136239.1:p.Glu1451fs
  • NP_001136240.1:p.Glu1471fs
  • NP_001136245.1:p.Glu1468fs
  • NP_001341333.1:p.Glu1469fs
  • NP_149045.3:p.Glu1491fs
  • NC_000010.10:g.55583016_55583017insATAGTATT
  • NC_000010.10:g.55583017_55583024dup
  • NM_001142764.2:c.4468_4475dup
  • NM_033056.3:c.4462_4469dup
  • NM_033056.3:c.4462_4469dupAATACTAT
Protein change:
E1422fs
Links:
dbSNP: rs774056663
NCBI 1000 Genomes Browser:
rs774056663
Molecular consequence:
  • NM_001142763.2:c.4483_4490dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142764.2:c.4468_4475dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142765.2:c.4255_4262dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142766.2:c.4453_4460dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142767.2:c.4342_4349dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142768.2:c.4402_4409dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142773.2:c.4393_4400dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354404.2:c.4396_4403dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_033056.4:c.4462_4469dup - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001142769.3:c.4409+1872_4409+1879dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001142770.3:c.4373+1872_4373+1879dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001142771.2:c.4388+1872_4388+1879dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001142772.2:c.4373+1872_4373+1879dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354411.2:c.4388+4129_4388+4136dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354420.2:c.4367+4129_4367+4136dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354429.2:c.4367+4129_4367+4136dup - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001384140.1:c.4368-3034_4368-3027dup - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000590716GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Likely pathogenic
(Jun 20, 2024) 		germlineclinical testing

Citation Link,

SCV001379388Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 25, 2024) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss.

Wang R, Han S, Khan A, Zhang X.

Genet Test Mol Biomarkers. 2017 May;21(5):316-321. doi: 10.1089/gtmb.2016.0328. Epub 2017 Mar 10.

PubMed [citation]
PMID:
28281779
PMCID:
PMC5444417

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From GeneDx, SCV000590716.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Frameshift variant predicted to result in protein truncation, as the last 465 amino acids are replaced with 10 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001379388.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change creates a premature translational stop signal (p.Glu1491Ilefs*11) in the PCDH15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 465 amino acid(s) of the PCDH15 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with PCDH15-related conditions. ClinVar contains an entry for this variant (Variation ID: 432938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the PCDH15 protein in which other variant(s) (p.Gln1576*) have been determined to be pathogenic (PMID: 28281779). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 8, 2024