ClinVar Miner

Submissions for variant NM_002476.2(MYL4):c.419G>A (p.Arg140His) (rs374127769)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000538814 SCV000656677 uncertain significance Atrial fibrillation, familial, 18 2017-08-21 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 140 of the MYL4 protein (p.Arg140His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs374127769, ExAC 0.006%) but has not been reported in the literature in individuals with a MYL4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786178 SCV000924886 uncertain significance not provided 2017-10-13 no assertion criteria provided provider interpretation p.Arg140His (c.419G>A) in exon 5 of the MYL4 gene (NM_001002841.1; chr17-45299153-G-A) SCICD Classification: variant of uncertain significance based on limited data to associate this gene with this patient's disease, lack of case data, lack of segregation data and relatively high frequency in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: MYL4: A single variant in MYL4 (p.Glu11Lys) segregated with disease in 6 individuals of one family with early-onset atrial fibrillation, conduction system disease and atrial myopathy (Orr et al, 2016). Functional studies in zebrafish demonstrated an atrial-specific cardiomyopathy and electrical abnormalities in line with atrial fibrillation in humans. No other sequence variants in MYL4 are reported in ClinVar. The clinical significance of other variants in MYL4 is therefore unknown. Case data (not including our patient): none · ClinVar: absent · Cases in the literature: none Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0")." Conservation data: The arginine at codon 140 is completely conserved across species. Neighboring amino acids are also completely conserved. Nearby pathogenic variants at this codon or neighboring codons: no other pathogenic sequence variants listed in ClinVar Population data: Highest MAF in European (non-Finnish) population: 0.012%. The variant was reported online in 14 of 123,106 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 13 of 55,842 individuals of European (non-Finnish) descent (MAF=0.012%) and 1 of 15,388 individuals of South Asian descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Given that the gnomAD cohort includes patients with atrial fibrillation, this variant cannot be discounted based on frequency alone.

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