ClinVar Miner

Submissions for variant NM_052867.4(NALCN):c.2563C>T (p.Arg855Ter)

gnomAD frequency: 0.00001  dbSNP: rs376152742
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000578635 SCV000681151 pathogenic not provided 2022-10-10 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29610177, 32943903, 35808948)
Ambry Genetics RCV000623970 SCV000742166 pathogenic Inborn genetic diseases 2020-01-14 criteria provided, single submitter clinical testing The alteration results in a premature stop codon: The c.2563C>T (p.R855*) alteration, located in exon 22 (coding exon 21) of the NALCN gene, results from a C to T substitution at nucleotide position 2563. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 855. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration has been observed in an affected individual: This alteration was reported in a patient with developmental delay, hypotonia, feeding difficulties, plagiocephaly, and disordered respiratory rhythm with central apnea (Campbell, 2018). Based on the available evidence, this alteration is classified as pathogenic.
Undiagnosed Diseases Network, NIH RCV001090146 SCV001245592 pathogenic Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 2019-09-19 criteria provided, single submitter clinical testing
Genetics Laboratory, Department of Biology, Semnan University RCV001090146 SCV001468667 pathogenic Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 2018-09-19 criteria provided, single submitter case-control The WES analysis identified a stop gain mutation in the NALCN gene on chromosome13 (NM_052867); chr13:101107503G/A c.2563C>T p.R855X (rs376152742). The mutation was predicted to be pathogenic by MutationTaster and CADD_phred. Our review of the public resources, local population database, and the literature revealed that there is no previous publication describing this mutation in homozygous form. However, a single ClinVar submission confirmed the pathogenic effects of this genetic anomaly but merely provided an overview of the resulting manifestations with no detailed information. Furthermore, it failed to distinguish between IHPRF1 and CLIFAHDD and resulted in confusion by referring to several publications on CLIFAHDD as supporting evidence (SCV000742166.1). Sanger sequencing confirmed the presence of the mutation and its homozygosity in the proband and segregated with the autosomal recessive inheritance pattern of IHPRF1 in all tested individuals.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine RCV001090146 SCV004047102 pathogenic Hypotonia, infantile, with psychomotor retardation and characteristic facies 1 criteria provided, single submitter clinical testing The stop gained variant has been reported previously in homozygous and compound heterozygous state in patients affected with Infantile hypotonia with psychomotor retardation and characteristic facies (Karimi et al). The c.2563C>T variant is reported with the allele frequency of 0.002123% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.2563C>T in NALCN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

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