ClinVar Miner

Submissions for variant NM_003480.4(MFAP5):c.472C>T (p.Arg158Ter)

gnomAD frequency: 0.00004  dbSNP: rs727502791
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374805 SCV001439506 likely pathogenic Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
3billion RCV000149579 SCV002058191 pathogenic Aortic aneurysm, familial thoracic 9 2022-01-03 criteria provided, single submitter clinical testing Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10% (PVS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:25434006, PS3_S). The variant has been reported to be associated with MFAP5 related disorder (ClinVar ID: VCV000162199, PMID:25434006).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Arcensus RCV000149579 SCV002564574 pathogenic Aortic aneurysm, familial thoracic 9 2013-02-01 criteria provided, single submitter clinical testing
MGZ Medical Genetics Center RCV000149579 SCV002581617 pathogenic Aortic aneurysm, familial thoracic 9 2022-07-27 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002516008 SCV003440434 likely pathogenic not provided 2023-05-05 criteria provided, single submitter clinical testing Experimental studies have shown that this premature translational stop signal affects MFAP5 function (PMID: 25434006). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 162199). This premature translational stop signal has been observed in individuals with MFAP5-related conditions (PMID: 25434006, 33824467). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs727502791, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Arg158*) in the MFAP5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 16 amino acid(s) of the MFAP5 protein.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000149579 SCV005087004 uncertain significance Aortic aneurysm, familial thoracic 9 2023-07-17 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with aortic aneurysm, familial thoracic 9, (MIM#616166). However, this gene-disease association is not yet established (PanelApp). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (11 heterozygotes, 0 homozygotes). (SP) 0600 - Variant results in the partial truncation of an annotated signal peptide (PMID: 33824467). (I) 0705 - No comparable protein truncating variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported once as a VUS (LOVD), but multiple times as likely pathogenic or pathogenic (ClinVar). It has also been observed in at least two unrelated individuals with aortic aneurysm or dissection (PMID: 25434006, PMID: 33824467), but also once in a healthy cohort (PMID: 29618732). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant has segregated in a single family, where seven individuals were either affected or ambiguously affected. However, there was also a healthy obligate carrier, and another ambiguously affected individual who did not have the variant (PMID: 25434006). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies on fibroblasts from affected individuals demonstrated a lack of extracellular protein otherwise observed in controls. This result was recapitulated in transfected HEK293 cells (PMID: 25434006). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM RCV000149579 SCV000196555 pathogenic Aortic aneurysm, familial thoracic 9 2014-12-04 no assertion criteria provided literature only

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