rs397516636

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM4_SupportingPP5

The NM_001195263.2(PDZD7):c.2675_2677delAGA(p.Lys892del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,535,908 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 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000043 ( 0 hom. )

Consequence

PDZD7
NM_001195263.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.47

Publications

0 publications found

Variant links:

Genes affected

PDZD7 (HGNC:26257): (PDZ domain containing 7) This gene encodes a ciliary protein homologous to proteins which are mutated in Usher syndrome patients, and mutations and translocations involving this gene have been associated with two types of Usher syndrome. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2010]

PDZD7 Gene-Disease associations (from GenCC):

hearing loss, autosomal recessive
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive 57
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
Usher syndrome type 2C
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

PDZD7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_001195263.2. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 10-101009290-ATCT-A is Pathogenic according to our data. Variant chr10-101009290-ATCT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44131.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDZD7	NM_001195263.2 link	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 16 of 17	ENST00000619208.6	NP_001182192.1	Q9H5P4-3
PDZD7	NM_001437429.1 link	c.2672_2674delAGA	p.Lys891del	disruptive_inframe_deletion	Exon 16 of 17		NP_001424358.1
PDZD7	XM_011540177.4 link	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 17 of 18		XP_011538479.1	Q9H5P4-3
PDZD7	XM_047425767.1 link	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 16 of 17		XP_047281723.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PDZD7	ENST00000619208.6 link	c.2675_2677delAGA	p.Lys892del	disruptive_inframe_deletion	Exon 16 of 17	5	NM_001195263.2	ENSP00000480489.1	Q9H5P4-3
PDZD7	ENST00000474125.7 link	n.2622_2624delAGA		non_coding_transcript_exon_variant	Exon 12 of 13	2		ENSP00000474447.1	S4R3J9
PDZD7	ENST00000474125.7 link	n.2622_2624delAGA		3_prime_UTR_variant	Exon 12 of 13	2		ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000365

AC:

AN:

136880

AF XY:

0.0000538

show subpopulations

Gnomad AFR exome

AF:

0.000155

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:

0.0000746

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000426

AC:

AN:

1383734

Hom.:

AF XY:

0.0000469

AC XY:

AN XY:

682816

show subpopulations

African (AFR)

AF:

0.0000317

AC:

AN:

31592

American (AMR)

AF:

0.00

AC:

AN:

35688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.00

AC:

AN:

35732

South Asian (SAS)

AF:

0.00

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000528

AC:

AN:

1078812

Other (OTH)

AF:

0.0000173

AC:

AN:

57906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.2675_2677del, results in the deletion of 1 amino acid(s) of the PDZD7 protein (p.Lys892del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397516636, gnomAD 0.02%). This variant has been observed in individual(s) with congenital sensorineural hearing loss (PMID: 34387732). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 44131). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -

Dec 17, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis does not support a benign or deleterious effect of this variant on protein structure/function; This variant is associated with the following publications: (PMID: 20440071, 36786328, 34387732) -

Hearing impairment

Pathogenic:1

May 29, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hearing loss, autosomal recessive 57

Pathogenic:1

Dec 01, 2019

Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 14, 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 Benign. The Lys892del in PD ZD7 has not been reported in the literature nor previously identified by our lab oratory. This variant results in an in-frame single amino acid deletion in exon 16 which is only present in an alternate longer transcript of PDZD7, with the ma jor transcript only encoding 10 exons. Furthermore, there is inconclusive eviden ce as to the role of the PDZD7 gene in hearing loss or Usher syndrome. No bialle lic mutations have been found in Usher patients to date despite screening in 205 cases (Ebermann 2010, Besnard 2012). Instead, there is one case report suggesti ng PDZD7 may be a modifier of the severity of Usher syndrome (Ebermann 2010). In addition, there is a second case report suggesting PDZD7 could cause nonsyndrom ic hearing loss based upon a patient with a homozygous translocation that disrup ts the long alternate isoform of PDZD7 (Schneider 2009). It should be noted that the affected individual did not have evidence of retinal disease at age 8 but a dditional evaluations beyond age 8 have not been reported. In summary, additiona l data is needed to determine the clinical significance of this variant; however , based upon the uncertain role of PDZD7 in hearing loss and Usher syndrome and the presence of an alternate cause of hearing loss in this patient, we would lea n towards a more likely benign role. -

PDZD7-related disorder

Uncertain:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PDZD7 c.2675_2677delAGA variant is predicted to result in an in-frame deletion (p.Lys892del). This variant was reported in the homozygous or compound heterozygous states along with a premature termination variant in three individuals with hearing loss from two families (Cruz Marino et al. 2022. PubMed ID: 34387732). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over