Submissions for variant NM_001164508.2(NEB):c.2510A>G (p.Lys837Arg)

gnomAD frequency: 0.00125  dbSNP: rs189623595

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000726043	SCV000341442	uncertain significance	not provided	2016-06-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001081649	SCV000417030	uncertain significance	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, 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.
GeneDx	RCV000726043	SCV000513910	likely benign	not provided	2020-12-17	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25203624)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081649	SCV000640748	likely benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000726043	SCV001747261	likely benign	not provided	2022-05-01	criteria provided, single submitter	clinical testing	NEB: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114451	SCV003800877	uncertain significance	not specified	2023-01-18	criteria provided, single submitter	clinical testing	Variant summary: NEB c.2510A>G (p.Lys837Arg) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00093 in 245282 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00093 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.2510A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluations, and classified as VUS (n=2) and Likely Benign (n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001081649	SCV001452186	likely benign	Nemaline myopathy 2	2019-11-11	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000726043	SCV001800474	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000726043	SCV001926567	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726043	SCV001967771	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549597	SCV004756150	benign	NEB-related disorder	2019-06-06	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).