Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000497608 | SCV000590688 | uncertain significance | not provided | 2022-01-26 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) |
| Labcorp Genetics |
RCV000497608 | SCV003482843 | uncertain significance | not provided | 2025-01-07 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg114*) in the MFAP5 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in MFAP5 cause disease. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of MFAP5-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 432913). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003330730 | SCV004039158 | likely pathogenic | Familial thoracic aortic aneurysm and aortic dissection | 2023-08-14 | criteria provided, single submitter | clinical testing | Variant summary: MFAP5 c.340C>T (p.Arg114X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are known mechanims for disease (PMID: 25434006). The variant allele was found at a frequency of 1.2e-05 in 251178 control chromosomes (i.e., 3 heterozygotes; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.340C>T in individuals affected with Thoracic Aortic Aneurysms And Dissections and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014, and both submitters classified the variant as uncertain significance, citing a lack sufficient evidence to establish loss-of-function variants in MFAP5 as causative of disease. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Ambry Genetics | RCV004023349 | SCV005020779 | uncertain significance | Cardiovascular phenotype | 2024-03-05 | criteria provided, single submitter | clinical testing | The p.R114* variant (also known as c.340C>T), located in coding exon 8 of the MFAP5 gene, results from a C to T substitution at nucleotide position 340. This changes the amino acid from an arginine to a stop codon within coding exon 8. This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of MFAP5 has not been established as a mechanism of disease. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. |