Submissions for variant NM_001271208.2(NEB):c.22275C>G (p.Tyr7425Ter)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Integrated Genetics/Laboratory Corporation of America	RCV000781648	SCV000919859	likely pathogenic	Nemaline myopathy	2018-11-29	criteria provided, single submitter	clinical testing	Variant summary: NEB c.22275C>G (p.Tyr7425X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.24407_24410dupTGTT (p.Leu8137fsX18), c.24559C>T (p.Arg8187X), and c.24632_24633delCT (p.Pro8211fsX4)). The variant allele was found at a frequency of 8.1e-06 in 245950 control chromosomes (gnomAD). The variant, c.22275C>G, has been reported in the literature in an individual affected with Nemaline Myopathy 2 (Pelin_2002). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000701148	SCV000829932	pathogenic	Nemaline myopathy 2	2018-03-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr7425) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs748922882, ExAC 0.009%). This variant has been reported in several individuals affected with nemaline myopathy (PMID:12207938, 16917880). This variant is also known as p.Tyr5689 in the literature. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.

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