chr10-53938872-G-A

Variant names:

• chr10-53938872-G-A
• rs202033121
• NM_033056.4:c.3316C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_033056.4(PCDH15):​c.3316C>T​(p.Arg1106*) 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:11
• Conservation: PhyloP100: 3.43
• Publications: 6 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: Pathogenic. The variant received 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 46464.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.3316C>T	p.Arg1106*	stop_gained	Exon 25 of 33	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3316C>T	p.Arg1106*	stop_gained	Exon 25 of 38	NP_001371069.1
	PCDH15	NM_001142763.2		c.3331C>T	p.Arg1111*	stop_gained	Exon 26 of 35	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3316C>T	p.Arg1106*	stop_gained	Exon 25 of 33	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3316C>T	p.Arg1106*	stop_gained	Exon 25 of 38	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3337C>T	p.Arg1113*	stop_gained	Exon 26 of 35	ENSP00000378832.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251140 AF XY: 0.0000221

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111622

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000101 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:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Usher syndrome type 1F Pathogenic:3

Oct 15, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 24, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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).

Aug 20, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

not provided Pathogenic:3

Mar 30, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 22, 2024

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.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.

Oct 23, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 18484607, 19375528)

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:2

Nov 22, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 11, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: flagged submission

Collection Method: research

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

May 18, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Usher syndrome Pathogenic:1

Dec 31, 2022

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Rare genetic deafness Pathogenic:1

Aug 15, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		3.4
Vest4		0.97
GERP RS		4.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

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