Submissions for variant NM_001271208.2(NEB):c.24444_24447del (p.Pro8149fs) (rs934111355)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000641305	SCV000762946	pathogenic	Nemaline myopathy 2	2019-07-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Pro8149Serfs*30) in the NEB gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another NEB variant in individuals affected with nemaline myopathy (PMID: 25205138, 26809617). This variant is also known as c.24339_24342del, p.Leu8113Leufs in the literature. ClinVar contains an entry for this variant (Variation ID: 533968). Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000641305	SCV000789370	pathogenic	Nemaline myopathy 2	2017-01-30	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000781650	SCV000919862	likely pathogenic	Nemaline myopathy	2017-11-27	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.24444_24447delACCT (p.Pro8149SerfsX30) variant results in a premature termination codon, predicted to cause a truncated or absent NEB 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.24559C>T [p.Arg8187X] and c.24632_24633delCT [p.Pro8211fsX4]). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/197362 control chromosomes at a frequency of 0.0000051, which does not exceed the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355). The variant, which is located in an alternatively spliced exon (Lehtokari_2014), has been reported in the literature in 2 compound heterozygous patients who had atypical and/or late onset of symptoms (Lehtokari_2014; Levesque_2016). Taken together, this variant is classified as likely pathogenic.

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