Submissions for variant NM_001164508.2(NEB):c.25367C>T (p.Thr8456Met)

gnomAD frequency: 0.00208  dbSNP: rs78592085

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724204	SCV000226194	uncertain significance	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202808	SCV000257875	uncertain significance	not specified	2015-07-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001080816	SCV000416806	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	RCV000202808	SCV000491010	uncertain significance	not specified	2016-12-02	criteria provided, single submitter	clinical testing	The T8491M variants in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. While not present in the homozygous state, the NHLBI Exome Sequencing Project reports T8491M was observed in 22/8232 (0.3%) alleles from individuals of European American background and the 1000 Genomes Project reports this variant was observed in 2/214 (0.9%) alleles from individuals of Italian ancestry, indicating it may be a rare variant in these populations. The T8491M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret T8491M as a variant of uncertain significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415163	SCV000492765	uncertain significance	Congenital muscular dystrophy; Muscle weakness	2014-05-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080816	SCV000640756	likely benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001080816	SCV001368244	uncertain significance	Nemaline myopathy 2	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000724204	SCV001714003	uncertain significance	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BS1
CeGaT Center for Human Genetics Tuebingen	RCV000724204	SCV004154105	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	NEB: BS2
PreventionGenetics, part of Exact Sciences	RCV004552967	SCV000307331	likely benign	NEB-related disorder	2019-06-05	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001080816	SCV001454422	likely benign	Nemaline myopathy 2	2020-01-13	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000724204	SCV001797665	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000724204	SCV001930026	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724204	SCV001963882	likely benign	not provided		no assertion criteria provided	clinical testing