ClinVar Miner

Submissions for variant NM_144612.6(LOXHD1):c.2998C>T (p.Arg1000Trp) (rs199847981)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766567 SCV000618381 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing The R1000W variant in the LOXHD1 gene has been reported previously with another LOXHD1 variant in an individual with autosomal recessive nonsyndromic hearing loss (Sommen et al., 2016). However, it was unknown if the two variants were on the same LOXHD1 allele (in cis) or on opposite alleles (in trans), and this individual was also reported to have two variants that were thought to be causative in another hearing loss gene (Sommen et al., 2016). The R1000W variant is observed in 8/8,596 (0.09%) alleles from individuals of European (non-Finnish) background in the ExAC dataset (Lek et al., 2016). The R1000W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. While this substitution occurs at a position that is not conserved, in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1000W as a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000520847 SCV000711095 uncertain significance not specified 2019-02-19 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Arg1000Trp va riant in LOXHD1 has been previously identified in 2 individuals with hearing los s (Sommen 2016, LMM data); however one of these individuals harbored two additio nal variants in the TECTA gene that were thought to be responsible for their hea ring loss (Sommen 2016). This variant has also been identified in 0.1% (92/76204 ) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computat ional prediction tools and conservation analysis do not provide strong support f or or against an impact to the protein. In summary, while the clinical significa nce of the p.Arg1000Trp variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting.

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