ClinVar Miner

Submissions for variant NM_144573.4(NEXN):c.1171C>T (p.Arg391Ter)

gnomAD frequency: 0.00001  dbSNP: rs200106758
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001241310 SCV001414319 pathogenic Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 2023-07-06 criteria provided, single submitter clinical testing This variant is present in population databases (rs200106758, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg391*) in the NEXN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEXN are known to be pathogenic (PMID: 32058062, 32814711, 32870709, 33949776). This premature translational stop signal has been observed in individual(s) with autosomal recessive dilated cardiomyopathy (PMID: 32870709). ClinVar contains an entry for this variant (Variation ID: 966591). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics RCV002224036 SCV002502974 uncertain significance not provided 2021-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV002327584 SCV002627737 uncertain significance Cardiovascular phenotype 2023-11-14 criteria provided, single submitter clinical testing The p.R391* variant (also known as c.1171C>T), located in coding exon 9 of the NEXN gene, results from a C to T substitution at nucleotide position 1171. This changes the amino acid from an arginine to a stop codon within coding exon 9. This variant was detected in the homozygous state in a child with dilated cardiomyopathy whose heterozygous parents were reportedly unaffected (Al-Hassnan ZN et al. Circ Genom Precis Med. 2020 10;13(5):504-514). This variant has also been reported to co-occur in trans with a second NEXN nonsense alteration in three fetuses affected with dilated cardiomyopathy (Kohaut E et al. Clin Genet. 2023 Jul;104(1):63-72). Although biallelic loss of function alterations in NEXN have been associated with autosomal recessive NEXN-related cardiomyopathy, haploinsufficiency for NEXN has not been clearly established as a mechanism of disease for autosomal dominant NEXN-related cardiomyopathy. Based on the supporting evidence, this variant is expected to be causative of autosomal recessive NEXN-related cardiomyopathy when present along with a second pathogenic variant on the other allele; however, its clinical significance for autosomal dominant NEXN-related cardiomyopathy is unclear.
Fulgent Genetics, Fulgent Genetics RCV001241310 SCV002776121 uncertain significance Dilated cardiomyopathy 1CC; Hypertrophic cardiomyopathy 20 2021-12-14 criteria provided, single submitter clinical testing

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