Submissions for variant NM_001271208.2(NEB):c.9467T>A (p.Ile3156Asn) (rs145770770)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000224006	SCV000281035	benign	not provided	2015-12-21	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000242273	SCV000307408	benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000242273	SCV000519843	benign	not specified	2016-03-03	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.
Athena Diagnostics Inc	RCV000242273	SCV000614186	likely benign	not specified	2017-05-23	criteria provided, single submitter	clinical testing
Invitae	RCV000557476	SCV000640898	benign	Nemaline myopathy 2	2019-12-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000242273	SCV001361229	benign	not specified	2019-04-22	criteria provided, single submitter	clinical testing	Variant summary: NEB c.9467T>A (p.Ile3156Asn) results in a non-conservative amino acid change in the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.011 in 280432 control chromosomes, predominantly at a frequency of 0.021 within the South Asian subpopulation in the gnomAD database, including 8 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 6-folds higher than 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 South Asian origin. To our knowledge, no occurrence of c.9467T>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.