ClinVar Miner

Submissions for variant NM_206933.3(USH2A):c.14753C>T (p.Thr4918Met) (rs56136489)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724181 SCV000231964 uncertain significance not provided 2014-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000724181 SCV000616915 uncertain significance not provided 2018-10-08 criteria provided, single submitter clinical testing The T4918M variant in the USH2A gene has been reported previously in an individual with Usher syndrome type II, however no information about a second variant was provided (McGee et al., 2010). The T4918M variant is observed in 14/6602 (0.212%) alleles from individuals of Finnish background and in 117/66710 (0.178%) alleles from individuals of non-Finnish European background including 1 homozygous individual, in the ExAC dataset (Lek et al., 2016). The T4918M 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. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T4918M as a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154359 SCV000204022 likely benign not specified 2015-07-30 criteria provided, single submitter clinical testing p.Thr4918Met in exon 67 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.2% (119/66710) of European chro mosomes, including 1 homozygous individual, by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs56136489). Threonine (Thr) at pos ition 4918 is not conserved in mammals or evolutionarily distant species and 1 m ammal (Pacific walrus) carries a methionine (Met) at this position, suggesting t his change may be tolerated. Additional computational prediction tools do not pr ovide strong support for or against an impact to the protein. Although this vari ant has been reported in one individual with Usher syndrome type II, the authors classified it as a variant of uncertain significance and did not clarify whethe r a second USH2A variant was found in the individual (McGee 2010).

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