ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.9619-2A>G (rs375145370)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000528659 SCV000789481 pathogenic Nemaline myopathy 2 2017-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000444827 SCV000515916 pathogenic not provided 2017-04-18 criteria provided, single submitter clinical testing The c.9619-2 A>G pathogenic variant in the NEB gene has been previouslyreported in trans with the exon 55 deletion in an individual with Nemaline myopathy (Yonath et al.,2012; Lehtokari et al., 2014). The c.9619-2 A>G pathogenic variant destroys the canonical spliceacceptor site in intron 66. It is predicted to cause abnormal gene splicing, either leading to anabnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal proteinproduct if the message is used for protein translation. The exon 55 deletion, including 2502nucleotides, results in an in-frame deletion of 35 amino acids and has previously been reported inmultiple Ashkenazi Jewish families with NEM (Anderson et al., 2004). This variant is considered pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000528659 SCV000914869 likely pathogenic Nemaline myopathy 2 2017-04-27 criteria provided, single submitter clinical testing The NEB c.8890-2A>G variant, also referred to as c.9619-2A>G, is reported in three studies and identified in five compound heterozygous individuals with nemaline myopathy including 3 siblings (Yonath et al. 2012; Lehtokari et al 2014; Feingold-Zadok et al. 2017). Control data are unavailable for this variant which is reported at a frequency of 0.000494 in the Ashkenazi Jewish population of the Genome Aggregation Database. Due to the potential impact of splice acceptor variants and the evidence from the literature, the c.8890-2A>G variant is classified as likely pathogenic for nemaline myopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Institute of Human Genetics,Klinikum rechts der Isar RCV000528659 SCV000680315 pathogenic Nemaline myopathy 2 2017-11-15 criteria provided, single submitter clinical testing
Invitae RCV000528659 SCV000640901 pathogenic Nemaline myopathy 2 2017-10-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 66 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Truncating variants in NEB are known to be pathogenic (PMID: 25205138), and this particular variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with severe congenital hypotonia (PMID: 22367672). For these reasons, this variant has been classified as Pathogenic.

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