Submissions for variant NM_001164508.2(NEB):c.20098C>A (p.Leu6700Ile)

gnomAD frequency: 0.00029  dbSNP: rs202139330

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193093	SCV000248153	uncertain significance	not specified	2014-04-29	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415257	SCV000492628	uncertain significance	Muscular dystrophy; Progressive proximal muscle weakness; Limb pain	2015-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000416246	SCV000493369	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000416246	SCV000531427	likely benign	not provided	2023-03-21	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687008	SCV000814556	benign	Nemaline myopathy 2	2024-01-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000687008	SCV001289003	uncertain significance	Nemaline myopathy 2	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000416246	SCV002010590	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000416246	SCV003810190	uncertain significance	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193093	SCV004813831	uncertain significance	not specified	2024-02-22	criteria provided, single submitter	clinical testing	Variant summary: NEB c.20098C>A (p.Leu6700Ile) results in a conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00041 in 248964 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00041 vs 0.0035), allowing no conclusion about variant significance. c.20098C>A has been reported in the literature in one individual with Fetal anomaly (example, Zhao_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. The following publication have been ascertained in the context of this evaluation (PMID: 33100332). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 211584). Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004020327	SCV004980069	uncertain significance	Inborn genetic diseases	2021-06-10	criteria provided, single submitter	clinical testing	The c.14995C>A (p.L4999I) alteration is located in exon 104 (coding exon 102) of the NEB gene. This alteration results from a C to A substitution at nucleotide position 14995, causing the leucine (L) at amino acid position 4999 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000416246	SCV005412892	uncertain significance	not provided	2023-12-08	criteria provided, single submitter	clinical testing	BP4
Natera, Inc.	RCV000687008	SCV001460615	likely benign	Nemaline myopathy 2	2020-04-30	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000416246	SCV001799949	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000416246	SCV001932129	uncertain significance	not provided		no assertion criteria provided	clinical testing