ClinVar Genomic variation as it relates to human health

The SLC26A4 c.1001+1G>A variant is a well-known splice donor variant that leads to aberrant splicing and accounts for approximately 14% of disease-causing alleles in persons of northern European descent (Alasti et al. 2014). Across a selection of the available literature, the c.1001+1G>A has been identified in a total of 53 individuals with hearing loss or Pendred syndrome, including four homozygotes, 17 compound heterozygotes, and 32 heterozygotes where a second variant was not identified (Coyle et al. 1998; Bogazzi et al. 2000; Campbell et al. 2001; Fugazzola et al. 2002; Tsukamoto et al. 2003; Bogazzi et al. 2004; Pryor et al. 2005; Madden et al. 2007; Pera et al. 2008; Pourova et al. 2010). The c.1001+1G>A variant is absent from over 500 controls and is reported at a frequency of 0.00052 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the c.1001+1G>A variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

The c.1001+1G>A variant in SLC26A4 has been previously described in the literatu re in individuals with Pendred syndrome/DFNB4 with well-established pathogenicit y (Coyle 1998, Campbell 2001, Bogazzi 2000, Lopez-Bigas 2001, Fugazzola 2002, Ts ukamoto 2003, Bogazzi 2004, Pryor 2005, Madden 2007, Pera 2008, Pourova 2010). T his variant is present in 47/125744 European chromosomes by the Genome Aggregati on Database; however, this frequency is low enough to be consistent with a carri er frequency for recessive hearing loss or Pendred syndrome (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs80338849). This variant occurs in the invariant r egion (+/- 1,2) of the splice consensus sequence and is predicted to cause alter ed splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4/Pend red syndrome based on the previously reported biallelic occurrences in affected individuals, association with specific clinical features, a low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria appl ied: PVS1, PS4.

The, NM_000441.1(SLC26A4):c.1001+1G>A heterozygous splice variant was identified in intron 8 of SLC26A4. This substitution is predicted to cause aberrant splicing of exon 8 in SLC26A4 and may result in a truncated protein; further testing via RNA studies are required to confirm if splicing is altered. The nucleotide at this position has moderate conservation (100 vertebrates, UCSC). In silico software predictions of the pathogenicity of this variant indicate this variant causes loss of a splice donor site (NetGene2, Fruit fly, Human Splicing Finder). This variant is present in the gnomAD population database at a frequency of 0.019% and it has been previously reported in patients with autosomal recessive Pendred syndrome (Clinvar/Deafness Variation Database). Based on current information and in association with the NM_000441.1(SLC26A4):c.707T>C missense variant , this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive Pendred syndrome.

NM_000441.1(SLC26A4):c.1001+1G>A is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 11317356 and 9618167. Classification of NM_000441.1(SLC26A4):c.1001+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.

This sequence change affects a donor splice site in intron 8 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs80338849, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 9618167, 24224479, 26744121). ClinVar contains an entry for this variant (Variation ID: 4819). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

PVS1_Strong, PS1_Strong, PM2_Supporting, PM3_Moderate, PP4_Supporting

Variant summary: SLC26A4 c.1001+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 250282 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.1001+1G>A has been reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coyle_1998, Pera_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 24224479, 10718825, 9618167, 22975760, 23273637, 25525159, 11919333, 18285825, 11317356, 14508505, 17309986, 20597900, 15689455, 25214170, 26744121, 20301640, 9618166, 30484383, 24963352, 31827275, 31980526, 31589614)

The SLC26A4 c.1001+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented as causative for Pendred syndrome and nonsyndromic hearing loss with enlarged vestibular aqueduct (EVA) (Coyle et al.1998. PubMed ID: 9618167; Ladsous et al. 2014. PubMed ID: 24224479; Beck et al. 2015. PubMed ID: 25214170). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in SLC26A4 are expected to be pathogenic. This variant is interpreted as pathogenic.

Variant interpreted as Pathogenic and reported on 04-26-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.