rs483352837

Positions:

• chr10-54023048-CACA-C
• chr10-54023048-CACA-CACAACA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The NM_033056.4(PCDH15):​c.2367_2369del​(p.Val790del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000849 in 1,613,888 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 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: PCDH15 NM_033056.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:7
• Conservation: PhyloP100: 6.08

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_033056.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 10-54023048-CACA-C is Pathogenic according to our data. Variant chr10-54023048-CACA-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126521.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=6}. Variant chr10-54023048-CACA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCDH15	NM_001384140.1	c.2367_2369del	p.Val790del	inframe_deletion	19/38	ENST00000644397.2
PCDH15	NM_033056.4	c.2367_2369del	p.Val790del	inframe_deletion	19/33	ENST00000320301.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCDH15	ENST00000320301.11	c.2367_2369del	p.Val790del	inframe_deletion	19/33	1	NM_033056.4
PCDH15	ENST00000644397.2	c.2367_2369del	p.Val790del	inframe_deletion	19/38		NM_001384140.1

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251246 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135776

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000862 AC: 126 AN: 1461770 Hom.: 0 AF XY: 0.0000866 AC XY: 63 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74366

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000126 Hom.: 0

Bravo AF: 0.0000642

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Usher syndrome type 1F Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 05, 2018	- -
Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 24, 2023	The p.Val790del variant in PCDH15 has been reported in 2 individuals with Usher syndrome type 1F (PMID: 32835555, 25930172) and has been identified in 0.02% (3/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs483352837). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#: 126521) and has been interpreted as pathogenic by Genomic Research Center (Shahid Beheshti University of Medical Sciences) and Institute of Otorhinolaryngology (Sun Yat-sen University) and as a variant of uncertain significance by Counsyl, Laboratory for Molecular Medicine (Mass General Brigham Personalized Medicine), Natera, Inc, and Women's Health and Genetics/Laboratory Corporation of America. Of the 2 affected individuals, 1 of those was a homozygote, which increases the likelihood that the p.Val790del variant is pathogenic (PMID: 25930172). This variant is a deletion of 1 amino acid at position 790 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP Criteria applied: PM4_supporting, PM3_supporting (Richards 2015). -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 10, 2020	- -

Autosomal recessive nonsyndromic hearing loss 23 Pathogenic:1 Uncertain:1

Pathogenic, flagged submission	literature only	Institute of Otorhinolaryngology, The First affiliated hospital, Sun Yat-sen University	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 30, 2023	- -

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This variant, c.2367_2369del, results in the deletion of 1 amino acid(s) of the PCDH15 protein (p.Val790del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs483352837, gnomAD 0.02%). This variant has been observed in individual(s) with PCDH15-related conditions (PMID: 25930172, 32835555). ClinVar contains an entry for this variant (Variation ID: 126521). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2023	In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25930172, 32835555) -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 10, 2020	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Val790del variant in PCDH15 has been previously reported in the homozygous state in one individual with sensorineural hearing loss and segregated in an affected family member. The affected individuals were reported to be age 18 and 28 years, and did not report symptoms of night-blindness. However, electroretinograms were not obtained (Zhan 2015 PMID: 25930172). It has also been identified in one individual with hearing loss by our laboratory who was heterozygous for the variant. This variant has been reported in ClinVar (Variation ID 126521), and it also has been identified in several populations by gnomAD, with the highest frequency of 0.01% (3/19950) of East Asian European chromosomes (http://gnomad.broadinstitute.org). This variant is a deletion of a valine (Val) residue at position 790 and is not predicted to alter the protein reading-frame. It is unclear whether this deletion impacts the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Val790del variant is uncertain. ACMG/AMP criteria applied: PM3_Supporting, PM2_Supporting, PP1, PM4_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 05, 2022	Variant summary: PCDH15 c.2367_2369delTGT (p.Val790del) results in an in-frame deletion that is predicted to remove one amino acid from Cadherin-like domain (IPR002126, also known as EC7 domain (Zhan_2015)) the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PCDH15 causing Usher Syndrome Type 1F (5.6e-05 vs 0.0032), allowing no conclusion about variant significance. c.2367_2369delTGT has been reported in the literature in one heterozygous individual affected with Usher Syndrome and one homozygous individual affected with non-syndromic hearing loss (Zhan_2015, Zheng_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs483352837; hg19: chr10-55782808;