VCV001472021.8 - ClinVar

NM_000138.5(FBN1):c.3661T>A (p.Cys1221Ser)

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Pathogenic

This classification is based on the single submission received

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000138.5(FBN1):c.3661T>A (p.Cys1221Ser)

Variation ID: 1472021 Accession: VCV001472021.8

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 15q21.1 15: 48485425 (GRCh38) [ NCBI UCSC ] 15: 48777622 (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	Mar 28, 2022	Feb 23, 2026	Aug 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000138.5:c.3661T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000129.3:p.Cys1221Ser	missense
NC_000015.10:g.48485425A>T
NC_000015.9:g.48777622A>T
NG_008805.2:g.165364T>A
LRG_778:g.165364T>A

... more HGVS ... less HGVS

Protein change

C1221S

Other names

Canonical SPDI

NC_000015.10:48485424:A:T

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.

Links

ClinGen: CA392324431 dbSNP: rs2141291310 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.
FBN1		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	8999	9394

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.
Familial thoracic aortic aneurysm and aortic dissection Marfan syndrome	Pathogenic (1)	criteria provided, single submitter	Aug 22, 2024	RCV002002794.8

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.	Expand all rows Collapse all rows 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 (Aug 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Marfan syndrome Familial thoracic aortic aneurysm and aortic dissection Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002255981.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 23, 2026	Publications: PubMed (5) PubMed: 16571647‚ 16905551‚ 17701892‚ 19349279‚ 31061752 Comment: show This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1221 of the FBN1 protein (p.Cys1221Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1472021). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant disrupts the p.Cys1221 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 31061752), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1221 of the FBN1 protein (p.Cys1221Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of FBN1-related conditions (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1472021). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FBN1 protein function with a positive predictive value of 95%. This variant affects a cysteine residue in the EGF-like, TGFBP or hybrid motif domains of FBN1. Cysteine residues are believed to be involved in intramolecular disulfide bridges and have been shown to be important for FBN1 protein structure (PMID: 16905551, 19349279). In addition, missense substitutions affecting cysteine residues within these domains are significantly overrepresented among patients with Marfan syndrome (PMID: 16571647, 17701892). This variant disrupts the p.Cys1221 amino acid residue in FBN1. Other variant(s) that disrupt this residue have been observed in individuals with FBN1-related conditions (PMID: 31061752), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Early-Onset Marfan Syndrome: A Case Series.	Ardhanari M	Journal of pediatric genetics	2019	PMID: 31061752
Latent transforming growth factor beta-binding proteins and fibulins compete for fibrillin-1 and exhibit exquisite specificities in binding sites.	Ono RN	The Journal of biological chemistry	2009	PMID: 19349279
Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study.	Faivre L	American journal of human genetics	2007	PMID: 17701892
Marfan syndrome-causing mutations in fibrillin-1 result in gross morphological alterations and highlight the structural importance of the second hybrid domain.	Mellody KT	The Journal of biological chemistry	2006	PMID: 16905551
The molecular genetics of Marfan syndrome and related disorders.	Robinson PN	Journal of medical genetics	2006	PMID: 16571647

Text-mined citations for rs2141291310 ...

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 Feb 24, 2026