Submissions for variant NM_001164508.2(NEB):c.3989A>G (p.Tyr1330Cys)

gnomAD frequency: 0.00071  dbSNP: rs189553632

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000545940	SCV000640791	likely benign	Nemaline myopathy 2	2025-02-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001574354	SCV001801158	uncertain significance	not provided	2024-08-16	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002525302	SCV003679057	uncertain significance	Inborn genetic diseases	2021-07-21	criteria provided, single submitter	clinical testing	The c.3989A>G (p.Y1330C) alteration is located in exon 37 (coding exon 35) of the NEB gene. This alteration results from a A to G substitution at nucleotide position 3989, causing the tyrosine (Y) at amino acid position 1330 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV001574354	SCV003812206	uncertain significance	not provided	2022-10-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330769	SCV004039298	uncertain significance	not specified	2023-08-24	criteria provided, single submitter	clinical testing	Variant summary: NEB c.3989A>G (p.Tyr1330Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00024 in 277944 control chromosomes (gnomAD), predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00024 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3989A>G in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics	RCV001574354	SCV004229804	uncertain significance	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
PreventionGenetics, part of Exact Sciences	RCV004553215	SCV004763792	likely benign	NEB-related disorder	2022-08-01	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).