VCV000162199.26 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(7)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(3); Likely pathogenic(2); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 162199 Accession: VCV000162199.26

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.31 12: 8648141 (GRCh38) [ NCBI UCSC ] 12: 8800737 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 11, 2015	Jul 23, 2024	Jul 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_003480.4:c.472C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003471.1:p.Arg158Ter	nonsense
NM_001297709.2:c.442C>T	NP_001284638.1:p.Arg148Ter	nonsense
NM_001297710.2:c.406C>T	NP_001284639.1:p.Arg136Ter	nonsense
NM_001297711.2:c.397C>T	NP_001284640.1:p.Arg133Ter	nonsense
NM_001297712.2:c.280C>T	NP_001284641.1:p.Arg94Ter	nonsense
NR_123733.2:n.743C>T		non-coding transcript variant
NR_123734.2:n.713C>T		non-coding transcript variant
NC_000012.12:g.8648141G>A
NC_000012.11:g.8800737G>A
NG_041814.1:g.19748C>T

... more HGVS ... less HGVS

Protein change

R158*, R133*, R136*, R148*, R94*

Other names

Canonical SPDI

NC_000012.12:8648140:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00000

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

ClinGen: CA295245 OMIM: 601103.0001 dbSNP: rs727502791 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LOC126861443	-	-	-	GRCh38	-	55
MFAP5		-	-	GRCh38 GRCh37	211	292

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Aortic aneurysm, familial thoracic 9	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jul 17, 2023	RCV000149579.16
Isolated thoracic aortic aneurysm	Likely pathogenic (1)	criteria provided, single submitter	Sep 1, 2018	RCV001374805.9
not provided	Likely pathogenic (1)	criteria provided, single submitter	May 5, 2023	RCV002516008.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic aneurysm, familial thoracic 9 Affected status: yes Allele origin: germline	MGZ Medical Genetics Center Accession: SCV002581617.1 First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 Comment: ACMG criteria applied: PVS1, PS3, PM2_SUP	Number of individuals with the variant: 1 Sex: male
Uncertain significance (Jul 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic aneurysm, familial thoracic 9 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005087004.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (3) PubMed: 25434006‚ 29618732‚ 33824467 Comment: 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 … (more) 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 (less)
Likely pathogenic (Sep 01, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Isolated thoracic aortic aneurysm Affected status: yes Allele origin: germline	Department of Vascular Biology, Beijing Anzhen Hospital Accession: SCV001439506.1 First in ClinVar: May 01, 2021 Last updated: May 01, 2021	Sex: mixed
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic aneurysm, familial thoracic 9 Affected status: yes Allele origin: germline	3billion Accession: SCV002058191.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:25434006 PMID:25434006 Comment: 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) 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. (less) Clinical Features: Stroke disorder (present)
Pathogenic (Feb 01, 2013)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Aortic aneurysm, familial thoracic 9 Affected status: yes Allele origin: germline	Arcensus Accession: SCV002564574.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Likely pathogenic (May 05, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003440434.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 25434006‚ 33824467 Comment: 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 … (more) 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. (less)
Pathogenic (Dec 04, 2014)	no assertion criteria provided Method: literature only	AORTIC ANEURYSM, FAMILIAL THORACIC 9 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000196555.1 First in ClinVar: Jan 11, 2015 Last updated: Jan 11, 2015	Publications: PubMed (1) PubMed: 25434006 Comment on evidence: In affected individuals from a 3-generation family segregating autosomal dominant thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.472C-T transition … (more) In affected individuals from a 3-generation family segregating autosomal dominant thoracic aortic aneurysm-9 (AAT9; 616166), Barbier et al. (2014) identified heterozygosity for a c.472C-T transition in exon 10 of the MFAP5 gene, resulting in an arg158-to-ter (R158X) substitution. The mutation was not found in unaffected family members. Analysis of patient fibroblasts demonstrated pure haploinsufficiency, and transfection studies confirmed that the R158X mutation abrogates protein production. (less)

Comment:

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

Comment:

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.

Comment:

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.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Evaluating the monogenic contribution and genotype-phenotype correlation in patients with isolated thoracic aortic aneurysm.	Li Y	European journal of human genetics : EJHG	2021	PMID: 33824467
KoVariome: Korean National Standard Reference Variome database of whole genomes with comprehensive SNV, indel, CNV, and SV analyses.	Kim J	Scientific reports	2018	PMID: 29618732
MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.	Barbier M	American journal of human genetics	2014	PMID: 25434006

Text-mined citations for rs727502791 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs727502791 ...