ClinVar Miner

Submissions for variant NM_016616.5(NME8):c.1277T>A (p.Leu426Ter)

gnomAD frequency: 0.00002  dbSNP: rs121918300
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002444419 SCV002682925 uncertain significance Primary ciliary dyskinesia 2019-09-17 criteria provided, single submitter clinical testing The p.L426* variant (also known as c.1277T>A), located in coding exon 13 of the NME8 gene, results from a T to A substitution at nucleotide position 1277. This changes the amino acid from a leucine to a stop codon within coding exon 13. This alteration was reported in a 13 year old girl with a clinical diagnosis of PCD and electron microscopy results showing that 66% of her respiratory cilia had shortened or absent outer dynein arms; a second disease-causing allele was not detected (Duriez B et al. Proc. Natl. Acad. Sci. U.S.A., 2007 Feb;104:3336-41). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of NME8 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Preventiongenetics, part of Exact Sciences RCV003415635 SCV004115497 likely pathogenic NME8-related condition 2023-03-03 criteria provided, single submitter clinical testing The NME8 c.1277T>A variant is predicted to result in premature protein termination (p.Leu426*). This variant has been reported in a patient with autosomal recessive primary ciliary dyskinesia (Duriez et al. 2007. PubMed ID: 17360648). This variant is reported in 0.043% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-37927908-T-A). Nonsense variants in NME8 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Invitae RCV000003412 SCV004278333 uncertain significance Primary ciliary dyskinesia 6 2023-10-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu426*) in the NME8 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in NME8 cause disease. This variant is present in population databases (rs121918300, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NME8-related conditions. ClinVar contains an entry for this variant (Variation ID: 3256). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
OMIM RCV000003412 SCV000023570 pathogenic Primary ciliary dyskinesia 6 2007-02-27 no assertion criteria provided literature only
GeneReviews RCV000003412 SCV000086969 not provided Primary ciliary dyskinesia 6 no assertion provided literature only

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