Submissions for variant NM_001164508.2(NEB):c.4198G>A (p.Ala1400Thr)

gnomAD frequency: 0.00047  dbSNP: rs113174390

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210578	SCV000263026	likely benign	Inborn genetic diseases	2013-12-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Eurofins Ntd Llc (ga)	RCV000309322	SCV000343560	uncertain significance	not provided	2016-08-23	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000534346	SCV000417003	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534346	SCV000640793	benign	Nemaline myopathy 2	2025-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000309322	SCV001765317	uncertain significance	not provided	2024-11-06	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004800338	SCV005422384	uncertain significance	not specified	2024-10-11	criteria provided, single submitter	clinical testing	Variant summary: NEB c.4198G>A (p.Ala1400Thr) results in a non-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 0.00019 in 249228 control chromosomes, predominantly at a frequency of 0.0014 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 (0.00019 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4198G>A in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 225110). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV000534346	SCV001462199	likely benign	Nemaline myopathy 2	2019-11-11	no assertion criteria provided	clinical testing