rs202033121

chr10-53938872-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033056.4(PCDH15):c.3316C>T(p.Arg1106Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1106R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PCDH15 NM_033056.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 3.43

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-53938872-G-A is Pathogenic according to our data. Variant chr10-53938872-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 46464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-53938872-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_033056.4	c.3316C>T	p.Arg1106Ter	stop_gained	25/33	ENST00000320301.11
PCDH15	NM_001384140.1	c.3316C>T	p.Arg1106Ter	stop_gained	25/38	ENST00000644397.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.3316C>T	p.Arg1106Ter	stop_gained	25/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.3316C>T	p.Arg1106Ter	stop_gained	25/38		NM_001384140.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251140 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135742

Gnomad AFR exome AF: 0.00

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: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461318 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 726990

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000110 Hom.: 0

Bravo AF: 0.00000756

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1F Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 15, 2021	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Arg1106Ter variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 19375528, 18484607) and has been identified in 0.004% (5/113538) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202033121). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 46464) and has been interpreted as pathogenic or likely pathogenic by Fulgent Genetics, Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Invitae, and Natera, Inc.. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Arg1106Ter variant is pathogenic (PMID: 19375528). This nonsense variant leads to a premature termination codon at position 1106, which is predicted to lead to a truncated or absent protein. Loss of function of the PCDH15 gene is an established disease mechanism in autosomal recessive Usher syndrome type 1F. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome type 1F. ACMG/AMP Criteria applied: PVS1, PM2_supporting, PM3_supporting (Richards 2015). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Aug 20, 2014	- -

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 18, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 25, 2023	This sequence change creates a premature translational stop signal (p.Arg1106*) in the PCDH15 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PCDH15 are known to be pathogenic (PMID: 11398101, 11487575, 14570705). This variant is present in population databases (rs202033121, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 18484607, 19375528). ClinVar contains an entry for this variant (Variation ID: 46464). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 30, 2022	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 18, 2017

- -

Usher syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Dec 31, 2022

- -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2017

The p.Arg1106X variant in PCDH15 has been reported in the homozygous state in on e individual with Usher syndrome type I (Ammar-Khodja 2009). It has also been id entified in 5/111450 European chromosomes by the Genome Aggregation Database (gn omAD, http://gnomad.broadinstitute.org; dbSNP rs202033121). Although this varian t has been seen in the general population, its frequency is low enough to be con sistent with a recessive carrier frequency. The p.Arg1106X variant leads to a pr emature stop codon at position 1106, which is predicted to lead to a truncated o r absent protein. In summary, this variant meets criteria to be classified as pa thogenic for autosomal recessive Usher syndrome based on the previously reported individual, low frequency in the general population, and predicted loss of func tion of the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.62
Cadd	Pathogenic	42
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.91	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;D;D;D;D
Vest4		0.97
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs202033121; hg19: chr10-55698632; COSMIC: COSV57269690;