rs397516633

Variant names:

• chr10-101010781-CT-C
• rs397516633
• NM_001195263.2:c.2107delA

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 9P and 1B. PVS1 PP5 BS2_Supporting

The NM_001195263.2(PDZD7):​c.2107delA​(p.Ser703ValfsTer20) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 0.0400
• Publications: 5 publications found

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)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 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 VariationId is 44121.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195263.2. 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
	PDZD7	NM_001195263.2	MANE Select	c.2107delA	p.Ser703ValfsTer20	frameshift	Exon 15 of 17	NP_001182192.1
	PDZD7	NM_001437429.1		c.2104delA	p.Ser702ValfsTer20	frameshift	Exon 15 of 17	NP_001424358.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PDZD7	ENST00000619208.6	TSL:5 MANE Select	c.2107delA	p.Ser703ValfsTer20	frameshift	Exon 15 of 17	ENSP00000480489.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2054delA		non_coding_transcript_exon	Exon 11 of 13	ENSP00000474447.1
	PDZD7	ENST00000474125.7	TSL:2	n.*2054delA		3_prime_UTR	Exon 11 of 13	ENSP00000474447.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152118 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.000305 AC: 40 AN: 131056 AF XY: 0.000306

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 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.: 2 Cov.: 41 AF XY: 0.000486 AC XY: 332 AN XY: 682544

African (AFR) AF: 0.0000317 AC: 1 AN: 31588

American (AMR) AF: 0.000616 AC: 22 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35730

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33474

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5660

European-Non Finnish (NFE) AF: 0.000561 AC: 605 AN: 1078858

Other (OTH) AF: 0.000328 AC: 19 AN: 57892

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74418

African (AFR) AF: 0.0000482 AC: 2 AN: 41534

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000280

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Jan 22, 2025

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.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.

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 29, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 04, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

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).

PDZD7-related disorder Pathogenic:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 IIC, GPR98/PDZD7 digenic Pathogenic:1

Mar 05, 2022

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Usher syndrome type 2A;C2931213:Usher syndrome type 2C;C4693893:Hearing loss, autosomal recessive 57 Pathogenic:1

Mar 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Retinal dystrophy Pathogenic:1

Jan 01, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.040

Splicing

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

Other links and lift over

dbSNP: rs397516633; hg19: chr10-102770538;