ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.24632_24633del (p.Pro8211fs) (rs555445835)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255925 SCV000322454 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing The c.24632_24633delCT pathogenic variant in the NEB gene has been reported previously (described as c.24527_24528delCT in an alternative transcript) in nemaline myopathy, in an affected individual who was compound heterozygous for the c.24527_24528delCT pathogenic variant and another NEB variant (Gajda et al., 2015). The c.24632_24633delCT variant causes a frameshift starting with Proline 8211, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Pro8211ArgfsX4. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.24632_24633delCT variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.24632_24633delCT as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000588377 SCV000697820 pathogenic Nemaline myopathy 2019-03-07 criteria provided, single submitter clinical testing Variant summary: NEB c.24632_24633delCT (p.Pro8211ArgfsX4) (also known as c.24527_24528delCT) 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. A truncation variant, c.25241T>G (p.Leu8414X), downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.4e-06 in 237000 control chromosomes (gnomAD). c.24632_24633delCT has been reported in the literature in multiple compound heterozygous individuals affected with Nemaline Myopathy 2 (Gajda 2013, 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. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000666987 SCV000935658 pathogenic Nemaline myopathy 2 2019-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Pro8211Argfs*4) 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: 24056153, 25205138). This variant is also known as c.24527_24528delCT in the literature. ClinVar contains an entry for this variant (Variation ID: 265493). Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV001270074 SCV001448851 pathogenic Low-set ears; Dysphagia; Abnormality of the neck 2019-09-09 criteria provided, single submitter clinical testing
Counsyl RCV000666987 SCV000791371 pathogenic Nemaline myopathy 2 2017-05-16 no assertion criteria provided clinical testing

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