Submissions for variant NM_001164508.2(NEB):c.17497G>A (p.Val5833Ile)

gnomAD frequency: 0.00187  dbSNP: rs149881695

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000238680	SCV000297089	uncertain significance	not specified	2015-07-20	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000238680	SCV000307259	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000552636	SCV000416918	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
GeneDx	RCV001535404	SCV000518456	likely benign	not provided	2020-09-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000552636	SCV000640597	likely benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000238680	SCV000857209	likely benign	not specified	2017-10-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000552636	SCV001653426	uncertain significance	Nemaline myopathy 2	2021-05-18	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000552636	SCV001984166	likely benign	Nemaline myopathy 2	2020-09-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000238680	SCV002819663	likely benign	not specified	2022-12-19	criteria provided, single submitter	clinical testing	Variant summary: NEB c.17497G>A (p.Val5833Ile) 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 0.0022 in 249108 control chromosomes, predominantly at a frequency of 0.0058 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 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 South Asian origin. c.17497G>A has been reported in the literature in individuals affected with prostate cancer as well as in controls (Karyadi_2017). The report does 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. Eight ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=2) and likely benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV001535404	SCV004154132	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NEB: BP4, BS2
Natera, Inc.	RCV000552636	SCV001454705	likely benign	Nemaline myopathy 2	2020-01-06	no assertion criteria provided	clinical testing