Submissions for variant NM_001271208.2(NEB):c.571G>C (p.Glu191Gln) (rs35686968)

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Total submissions: 5

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000117763	SCV000152020	uncertain significance	not provided	2013-08-23	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000250977	SCV000307367	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000250977	SCV000519544	benign	not specified	2016-05-31	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	RCV000552723	SCV000640823	benign	Nemaline myopathy 2	2017-08-08	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000250977	SCV000917877	benign	not specified	2018-08-06	criteria provided, single submitter	clinical testing	Variant summary: NEB c.571G>C (p.Glu191Gln) results in a conservative amino acid change located in the Nebulin repeat region of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.016 in 276052 control chromosomes in the gnomAD database, including 81 homozygotes. The observed variant frequency is approximately 4.65 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.571G>C in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites variant as "benign." Based on the evidence outlined above, the variant was classified as benign.

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