ClinVar Miner

Submissions for variant NM_004447.6(EPS8):c.2177C>T (p.Thr726Ile)

gnomAD frequency: 0.00041  dbSNP: rs150904526
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000605241 SCV000732022 uncertain significance not specified 2017-12-05 criteria provided, single submitter clinical testing The p.Thr726Ile variant in EPS8 has not been previously reported in individuals with hearing loss, but has been identified in 0.08% (100/126428) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs150904526). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr726Ile variant is uncertain. ACMG/AMP Criteria applied: None
Fulgent Genetics, Fulgent Genetics RCV000763826 SCV000894743 uncertain significance Autosomal recessive nonsyndromic hearing loss 102 2022-02-09 criteria provided, single submitter clinical testing
GeneDx RCV002509475 SCV002818814 uncertain significance not provided 2022-12-27 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV002509475 SCV003292358 uncertain significance not provided 2025-01-23 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 726 of the EPS8 protein (p.Thr726Ile). This variant is present in population databases (rs150904526, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with EPS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 517643). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt EPS8 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002531683 SCV003715238 uncertain significance Inborn genetic diseases 2024-11-24 criteria provided, single submitter clinical testing The c.2177C>T (p.T726I) alteration is located in exon 19 (coding exon 18) of the EPS8 gene. This alteration results from a C to T substitution at nucleotide position 2177, causing the threonine (T) at amino acid position 726 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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