ClinVar Genomic variation as it relates to human health

c.991-21TTC[2] (DFNA5; NM_004403.2; Chr7g.24746008_24746010delGAA; GRCh37): The c.991-21TTC[2] variant in DFNA5 has been reported in 4 Asian individuals with no n-syndromic sensorineural hearing loss, segregated with disease in 27 affected r elatives from 3 families and was absent in 440 Asian control chromosomes (Yu 200 3, Park 2010, Nisho 2014). It has also been previously identified by our laborat ory in one individual with hearing loss. This variant is a deletion of one unit of a trinucleotide (TTC) repeat sequence normally present as a triplicate (3 rep eat units), resulting in two copies of the TTC repeat. This variant is located i n the 3' splice region and has been shown to cause aberrant splicing, by skippin g of exon 8 (Yu 2003), which is predicted to lead to an abnormal or absent prote in. Several other variants in DFNA5 that have been reported to cause hearing los s are located in introns 7 or 8 and are expected to cause exon 8 skipping (Bisch off 2004, Van Laer 2005, Cheng 2007). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hearing loss based on the pr evious reports in affected individuals, segregations, and absence in controls.

Analysis of patient-derived RNA indicates that DFNA5/GSDME c.991-15_991-13delTTC weakens exon 8 splice acceptor, leading to loss of exon 8 in message and stop at codon 372 (Abu Rayyan 2020). The variant is heterozygous in 5 Palestinian children with progressive hearing loss, with average age at onset of 17 years. It is absent from 1300 Palestinian controls and from gnomAD v2.1.1.

The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24506266, 19911014, 14559215) and reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 19911014, 14559215). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000179997, PMID:14559215). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000041). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Published functional studies demonstrate adjacent exon 8 skipping and describe a hypothesized dominant-negative mechanism (Yu et al., 2003).; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes splice predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24506266, 14676472, 9771715, 17868390, 14559215, 29266521, 29849037, 32486382, 32747562, 19911014)

This sequence change falls in intron 7 of the DFNA5 gene. It does not directly change the encoded amino acid sequence of the DFNA5 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individuals with non-syndromic deafness (PMID: 14559215, 29266521). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 179997). Studies have shown that this variant results in skipping of exon 8 and introduces a new termination codon (PMID: 14559215). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

The GSDME:c.991-15_991-13delTTC splice variant is located 13 nucleotides upstream of exon 7 of the GSDME gene. This variant is classified as very rare in the overall population (allele frequency in gnomAD, v4.1.0= 0.000004114). The variant has been consistently classified as Pathogenic in nine entries in ClinVar (ClinVarID: 179997). The variant has been reported in several affected individuals with sensorineural with hearing loss and to co-segregate with the disease (PMID: 24506266, 19911014, 14559215). Experimental data suggest that the variant leads to skipping of exon 8 and thus to a non-functional protein (PMID: 14559215). In summary, this variant is classified as Pathogenic.