Submissions for variant NM_001271208.2(NEB):c.4407G>C (p.Glu1469Asp) (rs34800215)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000117758	SCV000269429	benign	not specified	2015-01-13	criteria provided, single submitter	clinical testing	p.Glu1469Asp in exon 38 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 4.8% (198/4134) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs34800215).
PreventionGenetics,PreventionGenetics	RCV000117758	SCV000307354	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000541913	SCV000417001	benign	Nemaline myopathy 2	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000117758	SCV000522709	benign	not specified	2016-03-12	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	RCV000541913	SCV000640799	benign	Nemaline myopathy 2	2019-12-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000117758	SCV001363582	benign	not specified	2019-04-01	criteria provided, single submitter	clinical testing	Variant summary: NEB c.4407G>C (p.Glu1469Asp) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.02 in 277192 control chromosomes in the gnomAD database, including 91 homozygotes. The observed variant frequency is approximately 6 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 benign. To our knowledge, no occurrence of c.4407G>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genetic Services Laboratory,University of Chicago	RCV000117758	SCV000152014	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.