Submissions for variant NM_001271208.2(NEB):c.24314_24317dup (p.Leu8106fs) (rs781667543)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542569	SCV000640739	pathogenic	Nemaline myopathy 2	2017-01-23	criteria provided, single submitter	clinical testing	This sequence change inserts 2 nucleotides in exon 172 of the NEB mRNA (c.24314_24317dup), causing a frameshift at codon 8106. This creates a premature translational stop signal (p.Leu8106Phefs*30) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported 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	RCV000588489	SCV000697817	likely pathogenic	Nemaline myopathy	2017-03-20	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.24314_24317dupTGTT (p.Leu8106Phefs) variant results in a premature termination codon, predicted to cause a truncated or absent NEB protein due to nonsense mediated decay, which are known disease mechanisms in nemaline myopathy. This variant is absent in 34482 control chromosomes from ExAC. This variant is reported in one family with typical nemaline myopathy in compound heterozygous state with c.1172_1173del (p.Tyr391*) (Lehtokari_2014). No genotypic and phenotypic details of the family members are provided in the study. It was also found in three colorectal cancer samples without confirmation of somatic status in COSMIC database. Truncations downstream of this position have been classified as pathogenic by our laboratory and other labs in ClinVar (e.g. p.Arg8187X, c.24771delT, c.24632_24633delCT). Taken together, this variant is classified as likely pathogenic.
Counsyl	RCV000542569	SCV001132441	likely pathogenic	Nemaline myopathy 2	2017-05-23	no assertion criteria provided	clinical testing

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