Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000538814 | SCV000656677 | uncertain significance | Atrial fibrillation, familial, 18 | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 140 of the MYL4 protein (p.Arg140His). This variant is present in population databases (rs374127769, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYL4-related conditions. ClinVar contains an entry for this variant (Variation ID: 476204). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
Stanford Center for Inherited Cardiovascular Disease, |
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. |