Submissions for variant NM_001164508.2(NEB):c.11164C>T (p.Arg3722Ter)

gnomAD frequency: 0.00001  dbSNP: rs928945364

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590386	SCV000697804	pathogenic	Nemaline myopathy	2016-09-09	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.11164C>T (p.Arg3722X) 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. Mutation taster predicts a damaging outcome for this variant. It is absent in 26806 control chromosomes while it was observed in affected patients in compound heterozygosity with other pathogenic NEB variants indicating causality. Taken together, this variant is classified as pathogenic.
Counsyl	RCV000674606	SCV000799972	pathogenic	Nemaline myopathy 2	2018-05-15	criteria provided, single submitter	clinical testing
Invitae	RCV000674606	SCV001583155	pathogenic	Nemaline myopathy 2	2023-08-29	criteria provided, single submitter	clinical testing	The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg3722*) 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 premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 496131).
MGZ Medical Genetics Center	RCV000674606	SCV002579487	likely pathogenic	Nemaline myopathy 2	2021-07-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003129932	SCV003816872	likely pathogenic	not provided	2022-02-21	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV003157724	SCV003845972	pathogenic	Arthrogryposis multiplex congenita 6		criteria provided, single submitter	clinical testing	A Heterozygous Nonsense variant c.10435C>T in Exon 72 of the NEB gene that results in the amino acid substitution p.Arg3479* was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as PathogenicLikelyPathogenic( variant ID 496131). This variant has been observed in many individuals affected with Arthrogryposis multiplex congenita 6 reported by(Lehtokari VL et al., 2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics	RCV003157724	SCV004200042	pathogenic	Arthrogryposis multiplex congenita 6	2023-10-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000674606	SCV002077091	pathogenic	Nemaline myopathy 2	2021-06-23	no assertion criteria provided	clinical testing