rs730880357

Positions:

chr10-53823041-G-GACTT

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

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).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

PCDH15
NM_033056.4 frameshift, stop_gained

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6

Conservation

PhyloP100: 1.37

Variant links:

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 links:

PCDH15 (HGNC:):

PCDH15 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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. Fraction of 0.202 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCDH15	NM_033056.4 linkuse as main transcript	c.4681_4684dupAAGT	p.Ser1562fs	frameshift_variant, stop_gained	33/33	ENST00000320301.11	NP_149045.3	Q96QU1-1
PCDH15	NM_001384140.1 linkuse as main transcript	c.4368-2815_4368-2812dupAAGT		intron_variant		ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11 linkuse as main transcript	c.4681_4684dupAAGT	p.Ser1562fs	frameshift_variant, stop_gained	33/33	1	NM_033056.4	ENSP00000322604.6		Q96QU1-1
PCDH15	ENST00000644397.2 linkuse as main transcript	c.4368-2815_4368-2812dupAAGT		intron_variant			NM_001384140.1	ENSP00000495195.1		A0A2R8Y6C0

Frequencies

GnomAD3 genomes

AF:

0.000296

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000757

AC:

AN:

251038

Hom.:

AF XY:

0.0000811

AC XY:

AN XY:

135718

show subpopulations

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 SAS 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:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000522

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000296

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74300

show subpopulations

Gnomad4 AFR

AF:

0.000869

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000105

Hom.:

Bravo

AF:

0.000314

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	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) -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 19, 2013	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2023	Variant summary: PCDH15 c.4681_4684dupAAGT (p.Ser1562X) located in the last exon 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. Athough observed in cohorts of individuals undergoing carrier screening (example, Perreault-Micale_2014) and nonsyndromic hearing loss (example, Quaio_2022), to our knowledge, no penetrant association 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. Furthermore, the Clingen Hearing Loss Working Group expert panel has reported a limited association of PCDH15 gene with non-syndromic hearing loss (06/19/2018) and truncating variants in the majority of the cytoplasmic domain of this gene have been reported as unlikely to cause Usher Syndrome 1F (Perreault-Micale_2014). The following publications have been ascertained in the context of this evaluation (PMID: 25307757, 36147510). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 30, 2024

- -

Autosomal recessive nonsyndromic hearing loss 23

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 16, 2021

- -

PCDH15-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 29, 2024

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. -

Usher syndrome type 1F

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over