ClinVar Miner

Submissions for variant NM_001164508.2(NEB):c.2920C>T (p.Arg974Ter)

gnomAD frequency: 0.00001  dbSNP: rs1553548666
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000530974 SCV000640767 pathogenic Nemaline myopathy 2 2024-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg974*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with fetal akinesia with lethal multiple pterygia syndrome (PMID: 25205138, 26578207). ClinVar contains an entry for this variant (Variation ID: 465594). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017670 SCV004848846 likely pathogenic Nemaline myopathy 2022-11-03 criteria provided, single submitter clinical testing The p.Arg974X variant in NEB has been reported in the homozygous state in consanguineous monoamniotic twin fetuses with severe hydrops, bilateral joint contractures, bilateral talipes, multiple pterygia, hypertelorism and cystic hygromas (Todd 2015 PMID: 26578207). It is absent from ClinVar but observed in 1/68012 European (non-Finnish) in gnomAD (https://gnomad.broadinstitute.org/). This nonsense variant leads to a premature termination codon at position 974, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism in autosomal recessive nemaline myopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive nemaline myopathy. ACMG/AMP Criteria applied: PM2_Supporting, PVS1.
OMIM RCV001449887 SCV000713852 pathogenic Arthrogryposis multiplex congenita 6 2021-05-27 no assertion criteria provided literature only
Counsyl RCV000530974 SCV000794613 likely pathogenic Nemaline myopathy 2 2017-10-02 no assertion criteria provided clinical testing

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