Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
King Laboratory, |
RCV003155017 | SCV003844112 | pathogenic | Autosomal recessive nonsyndromic hearing loss 4 | 2023-02-28 | criteria provided, single submitter | research | This variant was found in compound heterozygosity with an SLC26A4 missense variant that is known to be pathogenic, in a patient with bilateral sensorineural hearing loss of onset <18 years and bilateral enlarged vestibular aqueduct (EVA), in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no history of childhood-onset hearing loss. This variant is a single base pair substitution that is predicted to alter splicing. In a prior publication, functional analysis of RNA from lymphocytes of affected patients showed that this variant generates a new donor splice site, leading to mRNA with an insertion of six nucleotides from intron 4 of PDS (PMID: 10571950). As of January 2023, this variant has been reported previously in an individual with Pendred Syndrome and is currently classified as pathogenic to ClinVar, and it is found in 2 heterozygous individuals on gnomAD. Based on compound heterozygosity with a known pathogenic variant, evidence from prior functional studies, and goodness of fit of genotype to phenotype, we conclude that this variant is pathogenic. |
Invitae | RCV003555919 | SCV004294536 | pathogenic | not provided | 2023-04-25 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 4828). This variant is also known as 639+7A>G. This variant has been observed in individual(s) with SLC26A4-related conditions (PMID: 10571950, 22509691, 36633841). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs765884316, gnomAD 0.006%). This sequence change falls in intron 4 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. |
OMIM | RCV000005099 | SCV000025275 | pathogenic | Pendred syndrome | 1999-01-01 | no assertion criteria provided | literature only |