Submissions for variant NM_001271208.2(NEB):c.1623del (p.Asp542fs) (rs772366030)

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Total submissions: 2

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000697148	SCV000825744	pathogenic	Nemaline myopathy 2	2019-12-09	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp542Ilefs*15) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs772366030, ExAC 0.003%). This variant has been observed in two families affected with nemaline myopathy (PMID: 16917880, 25205138). ClinVar contains an entry for this variant (Variation ID: 575054). This variant is also known as g.37528delT 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.
Integrated Genetics/Laboratory Corporation of America	RCV001192839	SCV001361228	likely pathogenic	Nemaline myopathy	2019-02-15	criteria provided, single submitter	clinical testing	Variant summary: NEB c.1623delT (p.Asp542IlefsX15) 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 (e.g. c.2784delT (p.Asp929fsX28), c.11164C>T (p.Arg3722X), and c.21076C>T (p.Arg7026X)). The variant allele was found at a frequency of 4.1e-06 in 246074 control chromosomes (gnomAD). c.1623delT has been reported in the literature in two compound heterozygote families affected with Nemaline Myopathy 2 (Lehtokari_2014). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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