ClinVar Miner

Submissions for variant NM_001005373.4(LRSAM1):c.1913-1G>A

gnomAD frequency: 0.00003  dbSNP: rs756880678
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000693004 SCV000820857 pathogenic Charcot-Marie-Tooth disease axonal type 2P 2023-02-21 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 204301). Disruption of this splice site has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 20865121). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs756880678, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 23 of the LRSAM1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site results in altered splicing and introduces a premature termination codon (PMID: 20865121). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics Laboratory, London Health Sciences Centre RCV000192257 SCV001336729 pathogenic Charcot-Marie-Tooth disease criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001818450 SCV002064322 pathogenic not provided 2020-08-04 criteria provided, single submitter clinical testing DNA sequence analysis of the LRSAM1 gene demonstrated a sequence change in the canonical splice acceptor site of intron 23, c.1913-1G>A. This pathogenic sequence change is predicted to disrupt RNA splicing and likely to result in an absent or disrupted protein product (PMID: 20865121). This sequence change has been described in the gnomAD database with a low frequency of 0.005% in the European sub-population (dbSNP rs756880678). The majority of pathogenic variants in LRSAM1 are present in the heterozygous state and cause an autosomal dominant phenotype. However, this sequence change has been previously reported in the homozygous state segregating with disease in six affected individuals from one consanguineous family (PMID: 20865121).
Ambry Genetics RCV002408827 SCV002723303 pathogenic Inborn genetic diseases 2022-04-09 criteria provided, single submitter clinical testing The c.1913-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 23 of the LRSAM1 gene. This variant was found to segregate with autosomal recessive Charcot-Marie-Tooth disease, type 2P (CMT2P) in one family. Additionally, RNA studies demonstrated that this alteration results in a transcript expected to trigger nonsense-mediated mRNA decay (Guernsey DL et al. PLoS Genet, 2010 Aug;6). Based on the supporting evidence, this variant is expected to be causative of autosomal recessive CMT2P. However, loss of function of LRSAM1 has not been established as a mechanism of disease for autosomal dominant CMT2P, so the clinical significance for autosomal dominant CMT2P is unclear.
Inherited Neuropathy Consortium RCV000192257 SCV000928713 uncertain significance Charcot-Marie-Tooth disease no assertion criteria provided literature only

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