Variant rs397516633 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_001195263.2(PDZD7):c.2107delA(p.Ser703fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,535,548 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00047 ( 2 hom. )

Consequence

PDZD7
NM_001195263.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8U:1

Conservation

PhyloP100: 0.0400

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 10-101010781-CT-C is Pathogenic according to our data. Variant chr10-101010781-CT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44121.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=4, Likely_pathogenic=2}. Variant chr10-101010781-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PDZD7	NM_001195263.2 linkuse as main transcript	c.2107delA	p.Ser703fs	frameshift_variant	15/17	ENST00000619208.6	NP_001182192.1	Q9H5P4-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PDZD7	ENST00000619208.6 linkuse as main transcript	c.2107delA	p.Ser703fs	frameshift_variant	15/17	5	NM_001195263.2	ENSP00000480489.1	Q9H5P4-3
PDZD7	ENST00000474125.7 linkuse as main transcript	n.*2054delA		non_coding_transcript_exon_variant	11/13	2		ENSP00000474447.1	S4R3J9
PDZD7	ENST00000474125.7 linkuse as main transcript	n.*2054delA		3_prime_UTR_variant	11/13	2		ENSP00000474447.1	S4R3J9

Frequencies

GnomAD3 genomes

AF:

0.000270

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000305

AC:

AN:

131056

Hom.:

AF XY:

0.000306

AC XY:

AN XY:

71810

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000452

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:

0.000522

Gnomad OTH exome

AF:

0.000739

GnomAD4 exome

AF:

0.000468

AC:

648

AN:

1383312

Hom.:

Cov.:

AF XY:

0.000486

AC XY:

332

AN XY:

682544

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.000616

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:

0.000561

Gnomad4 OTH exome

AF:

0.000328

GnomAD4 genome

AF:

0.000269

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000280

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	This sequence change creates a premature translational stop signal (p.Ser703Valfs*20) in the PDZD7 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PDZD7 are known to be pathogenic (PMID: 20440071). This variant is present in population databases (rs397516633, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with non-syndromic hearing loss (PMID: 26849169). ClinVar contains an entry for this variant (Variation ID: 44121). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	The Ser703fs variant in PDZD7 is a frameshift variant that is predicted to alter the protein’s amino acid sequence beginning at position 703 and lead to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this variant has been reported in 0.7% (3/405) of healthy controls (Ebermann 2010), suggesting it is more likely benign, though this frequency is not high enough to rule out a pathogenic role. The variant occurs in exon 15 which is only present in an alternate longer transcript of PDZD7, with the major transcript only encoding 10 exons. Therefore, the impact of the truncated protein on biological function is unknown. Furthermore, there is inconclusive evidence as to the role of the PDZD7 gene in hearing loss or Usher syndrome. No biallelic mutations have been found in Usher patients to date despite screening in 205 cases (Ebermann 2010, Besnard 2012). Instead, there is one case report suggesting 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 nonsyndromic hearing loss based upon a patient with a homozygous translocation that disrupts 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 additional evaluations beyond age 8 have not been reported. In summary, additional data is needed to determine the clinical significance of this variant; however, based upon identification in 0.7% of controls we would lean towards a more likely benign interpretation. In addition, even if this variant was found to be disruptive to gene function and even if gene disruption was found to be linked to hearing loss or Usher syndrome, inheritance would most likely be recessive and there is currently no evidence of a pathogenic mutation on the second allele of the gene in this patient. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2023	Frameshift 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; This variant is associated with the following publications: (PMID: 20440071, 29048736, 26849169, 31454969, 34387732, 34948090, 36147510) -

Hearing loss, autosomal recessive 57

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The PDZD7 c.2107delA [p.S703fs] frameshift variant is predicted to result in premature truncation and/or absence of the PDZD7 protein and has previously been reported in prelingual, non-syndromic autosomal recessive hearing loss (PMID: 26849169). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 04, 2018	- -

Usher syndrome, type IIC, GPR98/PDZD7 digenic

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

The c.2107delA;p.(Ser703Valfs*20) is a null frameshift variant (NMD) in the PDZD7 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 44121; PMID: 26849169; PMID: 20440071) - PS4. The variant is present at low allele frequencies population databases (rs397516633 – gnomAD 0.003017%; ABraOM 0.001281 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Ser703Valfs*20) was detected in trans with a pathogenic variant (PMID: 26849169) and was detected in a homozygous state in the analyzed sample - PM3. The variant co-segregated with disease in multiple affected family members (PMID: 26849169) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic. -

PDZD7-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2024

The PDZD7 c.2107delA variant is predicted to result in a frameshift and premature protein termination (p.Ser703Valfs*20). This variant has been reported as pathogenic in patients with non-syndromic hearing loss (Vona et al. 2016. PubMed ID: 26849169; Cruz Marino et al. 2021. PubMed ID: 34387732). This variant is reported in 0.060% of alleles in individuals of Latino descent in gnomAD. Frameshift variants in PDZD7 are expected to be pathogenic and this variant has been interpreted as pathogenic or likely pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/44121). We interpret this variant as pathogenic. -

Usher syndrome type 2A;C2931213:Usher syndrome type 2C;C4693893:Hearing loss, autosomal recessive 57

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 28, 2022

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2022

- -

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