ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.3255+1G>T (rs375628303)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667228 SCV000791648 pathogenic Nemaline myopathy 2 2017-05-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000667228 SCV000893563 likely pathogenic Nemaline myopathy 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000667228 SCV000956305 pathogenic Nemaline myopathy 2 2018-09-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 32 of the NEB gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs375628303, ExAC 0.002%). This variant has been observed in individuals affected with nemaline myopathy (PMID: 16917880). This variant is also known as g.53437G>T in the literature. Experimental studies have shown that this splice donor change results in aberrant splicing of the NEB primary transcript (PMID: 16917880). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001199936 SCV001370723 pathogenic Nemaline myopathy 2020-05-18 criteria provided, single submitter clinical testing Variant summary: NEB c.3255+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in skipping of exon 32 (Lehtokari_2006). The variant allele was found at a frequency of 4e-06 in 248154 control chromosomes (gnomAD and publication). c.3255+1G>T has been reported in the literature in multiple individuals affected with Nemaline Myopathy (Lehtokari_2006, Lehtokari_2014). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

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