Submissions for variant NM_001195263.2(PDZD7):c.2211del (p.Gln737fs)

gnomAD frequency: 0.00004  dbSNP: rs1157689930

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004018298	SCV004847444	likely pathogenic	Nonsyndromic genetic hearing loss	2024-02-12	criteria provided, single submitter	clinical testing	The p.Gln737HisfsX16 variant in PDZD7 has not been previously reported in individuals with hearing loss but has been identified in 0.01% (6/41030) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2), consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 737 and leads to a premature termination codon 16 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the PDZD7 gene is an established disease mechanism in autosomal recessive hearing loss. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hearing loss. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.
Laboratory of Human Genetics, Universidade de São Paulo	RCV004719052	SCV005324781	pathogenic	Hearing loss, autosomal recessive	2024-05-01	criteria provided, single submitter	research	The PDZD7:NM_001195263.2:c.2211del variant is a null variant in a gene where loss of function is a known mechanism of disease (PVS1), it is associated with a recessive disorder, detected in trans with a pathogenic variant, in compound heterozygous state in affected cases (PM3), has extremely low frequency in gnomAD population databases (PM2), here it was found with c.166dup in two affected siblings born from unrelated couple.