Submissions for variant NM_001164508.2(NEB):c.23798T>C (p.Ile7933Thr)

dbSNP: rs140967744

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001131839	SCV001291479	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844268	SCV002103617	uncertain significance	not specified	2022-02-24	criteria provided, single submitter	clinical testing	Variant summary: NEB c.23903T>C (p.Ile7968Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 249028 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00015 vs 0.0035), allowing no conclusion about variant significance. c.23903T>C has been reported in the literature as a VUS compound heterozygous genotype (with NEB, c.21340C>T) in at-least one critically ill infant affected with Pneumonia, Hernia, Global Developmental delay, Atelectasis and Dysphagia who underwent trio genome sequencing analysis (example, Wang_2020). The authors reported the diagnostic criteria as needing follow-up. These report(s) do not provide unequivocal conclusions about association of the variant with Nemaline Myopathy 2. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001131839	SCV003250831	benign	Nemaline myopathy 2	2024-01-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV003132233	SCV003812805	uncertain significance	not provided	2021-08-23	criteria provided, single submitter	clinical testing