rs730880357

Variant names:

• chr10-53823041-G-GACTT
• rs730880357
• NM_033056.4:c.4681_4684dupAAGT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Strong PP5

The NM_033056.4(PCDH15):​c.4681_4684dupAAGT​(p.Ser1562fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1562S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: PCDH15 NM_033056.4 frameshift, stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 1.37
• Publications: 1 publications found

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 19 pathogenic variants in the truncated region.
• PP5: Variant 10-53823041-G-GACTT is Pathogenic according to our data. Variant chr10-53823041-G-GACTT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 179400.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.4681_4684dupAAGT	p.Ser1562fs	frameshift_variant, stop_gained	Exon 33 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.4368-2815_4368-2812dupAAGT		intron_variant	Intron 32 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.4681_4684dupAAGT	p.Ser1562fs	frameshift_variant, stop_gained	Exon 33 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.4368-2815_4368-2812dupAAGT		intron_variant	Intron 32 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000757 AC: 19 AN: 251038 AF XY: 0.0000811

Gnomad AFR exome AF: 0.000931

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000588 AC: 86 AN: 1461814 Hom.: 0 Cov.: 33 AF XY: 0.0000619 AC XY: 45 AN XY: 727206

African (AFR) AF: 0.000717 AC: 24 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111962

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.000229 AC XY: 17 AN XY: 74300

African (AFR) AF: 0.000869 AC: 36 AN: 41438

American (AMR) AF: 0.000393 AC: 6 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.000479 AC: 1 AN: 2086

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.000314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1F Pathogenic:1 Uncertain:1

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 20, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PCDH15 c.4681_4684dupAAGT (p.Ser1562X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 7.6e-05 in 251038 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (7.6e-05 vs 0.0032), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4681_4684dupAAGT in individuals affected with Usher Syndrome Type 1F and no experimental evidence demonstrating its impact on protein function have been reported. A downstream variant c.4726C>T p.Gln1576* has been reported to be Pathogenic for another PCDH15-related condition (nonsyndromic deafness, see PMID: 28281779) at Labcorp, suggesting loss of this region of the protein is deleterious. ClinVar contains an entry for this variant (Variation ID: 179400). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1 Uncertain:1

Aug 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 394 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Has not been previously published as pathogenic or benign with PCDH15-related condition to our knowledge; This variant is associated with the following publications: (PMID: 25307757, 15537665) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser1562*) in the PCDH15 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 394 amino acid(s) of the PCDH15 protein. This variant is present in population databases (rs730880357, gnomAD 0.09%). 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: 179400). 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. -

Usher syndrome type 1D;C1836027:Autosomal recessive nonsyndromic hearing loss 23;C1865885:Usher syndrome type 1F Pathogenic:1

Apr 30, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Nov 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The 4681_4684du pAAGT (Ser1562X) variant in PCDH15 has not been previously reported in individua ls with hearing loss, but has been identified in 0.02% (2/4262) of African Ameri can chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington. edu/EVS/). This variant leads to a premature termination codon at position 1562; however, the termination codon occurs within the last coding exon of the gene. Therefore, nonsense mediated decay is not expected to occur and the impact to pr otein function is unknown. In summary, the clinical significance of this variant cannot be determined with certainty; however, based upon the predicted loss of 394 amino acids in the last exon of PCDH15, we would lean towards a more likely pathogenic role. -

Autosomal recessive nonsyndromic hearing loss 23 Uncertain:1

Dec 16, 2021

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PCDH15-related disorder Uncertain:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PCDH15 c.4681_4684dupAAGT variant is predicted to result in premature protein termination (p.Ser1562*). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.089% of alleles in individuals of African descent in gnomAD. This variant occurs in the last exon of the PCDH15 alternatively spliced transcript known as CD1 (NM_033056), but this exon is not required for proper inner ear hair cell function and maintenance of hearing and is not included in the biologically relevant transcript for hearing loss known as CD2 (NM_001142769; Webb et al. 2011. PubMed ID: 21427143; Pepermans et al. 2014. PubMed ID: 24940003). Furthermore, loss of function variants in this exon of CD1 have been shown to occur at population frequencies inconsistent with pathogenicity (Perreault-Micale et al. 2014. PubMed ID: 25307757). This variant is interpreted as suspected benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=21/179	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730880357; hg19: chr10-55582801;