ClinVar Miner

Submissions for variant NM_002397.5(MEF2C):c.44G>A (p.Arg15His)

dbSNP: rs1202957297
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Génétique des Maladies du Développement, Hospices Civils de Lyon RCV000760219 SCV000890049 likely pathogenic Intellectual disability, autosomal dominant 20 2017-10-20 criteria provided, single submitter clinical testing
GeneDx RCV001592945 SCV001826753 pathogenic not provided 2024-07-29 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36403551, 34022131)
Ambry Genetics RCV004027172 SCV004902654 pathogenic Inborn genetic diseases 2023-11-02 criteria provided, single submitter clinical testing The c.44G>A (p.R15H) alteration is located in exon 2 (coding exon 1) of the MEF2C gene. This alteration results from a G to A substitution at nucleotide position 44, causing the arginine (R) at amino acid position 15 to be replaced by a histidine (H). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with MEF2C-related neurodevelopmental disorder (external communication). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). Based on internal structural analysis, R15H is a critical residue to DNA-binding in MEF2C (Santelli, 2000; Lei, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000760219 SCV002267971 uncertain significance Intellectual disability, autosomal dominant 20 2021-04-21 flagged submission clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MEF2C-related conditions. ClinVar contains an entry for this variant (Variation ID: 620015). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with histidine at codon 15 of the MEF2C protein (p.Arg15His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine.

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