Submissions for variant NM_001164508.2(NEB):c.21685G>C (p.Asp7229His)

gnomAD frequency: 0.00182  dbSNP: rs201979610

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174203	SCV000225464	uncertain significance	not provided	2014-11-19	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000174203	SCV000280950	uncertain significance	not provided	2015-02-10	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000259106	SCV000513919	likely benign	not specified	2017-06-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001086723	SCV000640692	likely benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001086723	SCV001296186	uncertain significance	Nemaline myopathy 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000259106	SCV002500385	likely benign	not specified	2022-03-14	criteria provided, single submitter	clinical testing	Variant summary: NEB c.21790G>C (p.Asp7264His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0018 in 280538 control chromosomes, predominantly at a frequency of 0.0036 within the Non-Finnish European subpopulation in the gnomAD database, including one homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.02 fold of the estimated maximal expected allele frequency for a pathogenic variant in NEB causing Nemaline Myopathy 2 phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.21790G>C has been reported in the literature in individuals affected with mild Nemaline Myopathy, sporadic distal myopathy and dilated cardiomyopathy (Wallgren-Pettersson_ 2004, Minoche_2019, Morales_2021). These reports do not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed this variant since 2014: two classified the variant as of uncertain significance and three as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000174203	SCV004699351	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004552961	SCV004736110	likely benign	NEB-related disorder	2023-01-20	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001086723	SCV001460594	likely benign	Nemaline myopathy 2	2020-01-11	no assertion criteria provided	clinical testing