Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Fulgent Genetics, |
RCV000667209 | SCV000893564 | pathogenic | Nemaline myopathy 2 | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781651 | SCV000919863 | pathogenic | Nemaline myopathy | 2017-12-11 | criteria provided, single submitter | clinical testing | Variant summary: The NEB c.78+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/245790 control chromosomes (gnomAD) at a frequency of 0.0000081, which does not exceed the estimated maximal expected allele frequency of a pathogenic NEB variant (0.0035355). Multiple publications have cited the variant in affected compound heterozygote and homozygote patients presenting with various severities of NEM2. The variant of interest has not, to our knowledge, been cited by clinical diagnostic laboratories, although HGMD cites the variant as "disease-causing." Taken together, this variant is classified as pathogenic. |
Invitae | RCV000667209 | SCV001578888 | pathogenic | Nemaline myopathy 2 | 2024-01-09 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 4 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs778593702, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with nemaline myopathy (PMID: 19232495, 25205138). ClinVar contains an entry for this variant (Variation ID: 552018). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
Revvity Omics, |
RCV001784246 | SCV002018276 | pathogenic | not provided | 2020-06-02 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000667209 | SCV002060171 | pathogenic | Nemaline myopathy 2 | 2021-11-15 | criteria provided, single submitter | clinical testing | NM_001271208.1(NEB):c.78+1G>A is a canonical splice variant classified as pathogenic in the context of NEB-related nemaline myopathy. c.78+1G>A has been observed in cases with relevant disease (PMID: 25205138, 30859559). Functional assessments of this variant are not available in the literature. c.78+1G>A has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, NM_001271208.1(NEB):c.78+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Baylor Genetics | RCV003465467 | SCV004200213 | pathogenic | Arthrogryposis multiplex congenita 6 | 2023-07-12 | criteria provided, single submitter | clinical testing | |
Prevention |
RCV004547838 | SCV004732288 | pathogenic | NEB-related disorder | 2023-12-27 | criteria provided, single submitter | clinical testing | The NEB c.78+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in patients with nemaline myopathy (Lehtokari et al. 2009. PubMed ID: 19232495; Pagnamenta et al. 2019. PubMed ID: 30859559; Lehtokari et al. 2014. PubMed ID: 25205138). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in NEB are expected to be pathogenic. This variant is interpreted as pathogenic. |
Natera, |
RCV000667209 | SCV002077875 | pathogenic | Nemaline myopathy 2 | 2020-12-01 | no assertion criteria provided | clinical testing |