ClinVar Miner

Submissions for variant NM_170707.4(LMNA):c.3G>A (p.Met1Ile)

dbSNP: rs794728598
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579197 SCV000680546 pathogenic not provided 2021-12-28 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Alters the initiator methionine codon, and the resultant protein would be described as "p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 488705; ClinVar)
Labcorp Genetics (formerly Invitae), Labcorp RCV000653926 SCV000775816 pathogenic Charcot-Marie-Tooth disease type 2 2023-10-13 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the LMNA mRNA. The next in-frame methionine is located at codon 187. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with LMNA-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 488705). This variant disrupts a region of the LMNA protein in which other variant(s) (p.Lys32del, p.Asn39Ser. p.Glu82Lys) have been determined to be pathogenic (PMID: 17377071, 18551513, 20160190, 20980393, 21632249). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations RCV001268969 SCV001448193 pathogenic See cases 2020-11-30 criteria provided, single submitter clinical testing We observed the genetic variant c.3G>A (p.M1I) in a 43-y.o. male proband, diagnosed with left ventricular non-compaction and dilatation of all cardiac chambers. The c.3G>A genetic variant leads to mutation in the initiation codon (PVS1 criteria). Neither population data (PM2 criteria) nor functional studies are available for this variant. Online in silico tools predict the p.M1I to have the deleterious effect (PP3 criteria). Additionally, this variant was previously reported as pathogenic (PP5). Two more nucleotide changes were reported in this codon, all of them leading to methionine-isoleucine amino acid substitution. We classify the c.3G>A genetic variant as pathogenic due to the combination of PVS1, PM2, PP3, and PP5 criteria.
KTest Genetics, KTest RCV001594399 SCV001499964 pathogenic Dilated cardiomyopathy 1A no assertion criteria provided clinical testing

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