Submissions for variant NM_001164508.2(NEB):c.22489C>T (p.Arg7497Ter)

gnomAD frequency: 0.00001  dbSNP: rs760935667

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672682	SCV000797814	likely pathogenic	Nemaline myopathy 2	2018-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781656	SCV000919868	likely pathogenic	Nemaline myopathy	2023-03-08	criteria provided, single submitter	clinical testing	Variant summary: NEB c.22594C>T (p.Arg7532X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248744 control chromosomes (gnomAD). he variant, c.22594C>T, has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV001784275	SCV002018285	pathogenic	not provided	2019-11-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001784275	SCV002064463	likely pathogenic	not provided	2018-07-09	criteria provided, single submitter	clinical testing	DNA sequence analysis of the NEB gene demonstrated a sequence change, c.17386C>T, which results in the creation of a premature stop codon at amino acid position 5796, p.Arg5796*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NEB protein with potentially abnormal function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000672682	SCV002126357	pathogenic	Nemaline myopathy 2	2023-04-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556650). This variant is also known as p.Arg7497*. This premature translational stop signal has been observed in individual(s) with NEB-related conditions (PMID: 25205138). This variant is present in population databases (rs760935667, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg7532*) 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).
Illumina Laboratory Services, Illumina	RCV001784275	SCV003802800	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	The NEB c.22489C>T (p.Arg7497Ter) nonsense variant results in the substitution of arginine at amino acid position 7497 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant, also referred to as c.22594C>T (p.Arg7532Ter), has been reported in one individual with nemaline myopathy (PMID: 25205138). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000008 in the Total population (version 2.1.1). Based on the available evidence, the c.22489C>T (p.Arg7497Ter) variant is classified as pathogenic for nemaline myopathy.
GeneDx	RCV001784275	SCV003927506	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Identified in a patient with the typical form of nemaline myopathy, although additional clinical information was not included (Lehtokari et al., 2014); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 25205138)
Baylor Genetics	RCV003472148	SCV004200239	pathogenic	Arthrogryposis multiplex congenita 6	2023-06-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000672682	SCV001463284	likely pathogenic	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing