ClinVar Miner

Submissions for variant NM_001271208.2(NEB):c.19944G>A (p.Ser6648=) (rs201553266)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224886 SCV000280967 pathogenic not provided 2014-08-13 criteria provided, single submitter clinical testing
GeneDx RCV000224886 SCV000329870 pathogenic not provided 2021-05-15 criteria provided, single submitter clinical testing Cryptic splice site that introduces a premature stop codon in gene for which loss-of-function is a known mechanism of disease (Oliveira et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 9536098, 17576681, 32721234, 32222963, 26841830, 26403434, 25205138)
Invitae RCV000541914 SCV000640653 pathogenic Nemaline myopathy 2 2020-09-25 criteria provided, single submitter clinical testing This sequence change affects codon 6648 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. This variant also falls at the last nucleotide of exon 129 of the NEB coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs201553266, ExAC 0.009%). This variant has been observed in individuals affected with nemaline myopathy (PMID: 25205148, Invitae). ClinVar contains an entry for this variant (Variation ID: 235402). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000224886 SCV000705513 uncertain significance not provided 2017-02-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000622763 SCV000740914 likely pathogenic Inborn genetic diseases 2015-06-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780536 SCV000917874 pathogenic Nemaline myopathy 2018-06-12 criteria provided, single submitter clinical testing Variant summary: NEB c.19944G>A (p.Ser6648Ser) alters a non-conserved nucleotide that is the last nucleotide of an exon and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site, while two predict the variant weakens a 5' donor site. These predictions are supported by functional evidence reported by Oliveira_2016 using whole blood from a homozygous patient, which showed the preferential use of a cryptic splice site, leading to a predicted truncation of the protein. Truncations downstream of this variant have been classified as pathogenic by our laboratory (e.g., p.Arg7026X and p.Leu8137fsX18). The variant allele was found at a frequency of 2.9e-05 in 245250 control chromosomes, which does not exceed the maximal expected allele frequency for a pathogenic variant in NEB. c.19944G>A has been reported in the literature in several individuals affected with Nemaline Myopathy 2, including both homozygous and compound heterozygous patients, indicating that the variant is likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, including pathogenic (1x), likely pathogenic (2x), and VUS (1x). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000541914 SCV001132257 likely pathogenic Nemaline myopathy 2 2018-07-30 no assertion criteria provided clinical testing

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