ClinVar Miner

Submissions for variant NM_001166345.3(MDFIC):c.391dup (p.Met131fs)

dbSNP: rs562142736
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV002279857 SCV004046198 pathogenic Lymphatic malformation 12 criteria provided, single submitter clinical testing This variant results in a c.391dup (p.Met131) change in an alternate MDFIC transcript NM_001166345.1. This frameshifting variant in exon 4 of 5 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a homozygous and compound heterozygous change in patients with Central conducting lymphatic anomaly (PMID: 35235341). Functional studies confirm this variant results in a truncated protein (PMID: 35235341). The c.718dup (p.Met240AsnfsTer3) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.01770% (50/282438) and thus is presumed to be rare. Based on the available evidence, the c.718dup (p.Met240AsnfsTer3) variant is classified as Pathogenic.
Institute of Human Genetics, Cologne University RCV002279857 SCV005331506 pathogenic Lymphatic malformation 12 2024-09-20 criteria provided, single submitter clinical testing
OMIM RCV002279857 SCV002567898 pathogenic Lymphatic malformation 12 2022-08-23 no assertion criteria provided literature only
PreventionGenetics, part of Exact Sciences RCV003418436 SCV004116381 likely pathogenic MDFIC-related disorder 2024-08-19 no assertion criteria provided clinical testing The MDFIC c.718dupA variant is predicted to result in a frameshift and premature protein termination (p.Met240Asnfs*3). Using an alternate transcript (NM_001166345), this variant is also referred to as c.391dupA (p.Met131Asnfs*3) in the literature. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with central conducting lymphatic anomaly with lymphedema (Byrne et al. 2022. PubMed ID: 35235341). Functional studies reveal that this variant escapes nonsense mediated decay, resulting in a truncated protein (Byrne et al. 2022. PubMed ID: 35235341). This variant is reported in 0.026% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic.

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