Submissions for variant NM_001164508.2(NEB):c.5971C>T (p.His1991Tyr)

gnomAD frequency: 0.04908  dbSNP: rs75807392

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000117767	SCV000307374	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000309553	SCV000416981	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	RCV000117767	SCV000519522	benign	not specified	2016-01-30	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000117767	SCV000711417	benign	not specified	2014-11-26	criteria provided, single submitter	clinical testing	p.His1991Tyr in exon 47 of NEB: This variant is not expected to have clinical si gnificance because it has been identified in 5.4% (442/8180) of European America n chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.ed u/EVS/) and in 26% (148/572) of Asian chromosomes by the 1000 Genomes Project (d bSNP rs75807392).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000117767	SCV000917871	benign	not specified	2017-09-25	criteria provided, single submitter	clinical testing	Variant summary: The NEB c.5971C>T (p.His1991Tyr) variant involves the alteration of a non-conserved nucleotide that is the first exonic nucleotide at an exon-intron junction. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) and 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 20328/251662 control chromosomes (1289 homozygotes) at a frequency of 0.080775, which is approximately 23 times the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355), strongly suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Invitae	RCV000309553	SCV001716709	benign	Nemaline myopathy 2	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001542878	SCV001761274	benign	Arthrogryposis multiplex congenita 6	2021-07-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000309553	SCV001761275	benign	Nemaline myopathy 2	2021-07-10	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477293	SCV002794897	benign	Nemaline myopathy 2; Arthrogryposis multiplex congenita 6	2021-07-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000117767	SCV000152024	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.
Natera, Inc.	RCV000309553	SCV001453485	benign	Nemaline myopathy 2	2020-09-16	no assertion criteria provided	clinical testing