NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 15, 2023
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000161118.18

Allele description [Variation Report for NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)]

NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

Genes:

LOC126862124:CDK7 strongly-dependent group 2 enhancer GRCh37_chr15:48764566-48765765 [Gene]
FBN1:fibrillin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.1

Genomic location:

Preferred name:

NM_000138.5(FBN1):c.4270C>G (p.Pro1424Ala)

Other names:

p.P1424A:CCA>GCA

HGVS:

NC_000015.10:g.48472617G>C
NG_008805.2:g.178172C>G
NM_000138.5:c.4270C>GMANE SELECT
NP_000129.3:p.Pro1424Ala
NP_000129.3:p.Pro1424Ala
LRG_778t1:c.4270C>G
LRG_778:g.178172C>G
LRG_778p1:p.Pro1424Ala
NC_000015.9:g.48764814G>C
NM_000138.4:c.4270C>G
c.4270C>G

Protein change:

P1424A

Links:

dbSNP: rs201273753

NCBI 1000 Genomes Browser:

rs201273753

Molecular consequence:

NM_000138.5:c.4270C>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Mus musculus olfactory receptor family 11 subfamily H member 4 (Or11h4), mRNA
Mus musculus olfactory receptor family 11 subfamily H member 4 (Or11h4), mRNA
gi|225735558|ref|NM_020288.2|

Nucleotide
Same Parent, Connectivity for PubChem Compound (Select 91115935) (888)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000058836	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Oct 21, 2013)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11524736, 9399842, 14695540, 16222657, 24033266
SCV000695537	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (May 15, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 26621581, 27153395, 26787436 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000058836

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Oct 21, 2013)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000695537

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(May 15, 2023)

germline

clinical testing

PubMed (14)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	2	1	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Detection of six novel FBN1 mutations in British patients affected by Marfan syndrome.

Comeglio P, Evans AL, Brice GW, Child AH.

Hum Mutat. 2001 Sep;18(3):251. Corrected and republished in: Hum Mutat. 2001 Dec;18(6):546-7. doi: 10.1002/humu.1235.

PubMed [citation]

PMID:: 11524736

Identification of sixty-two novel and twelve known FBN1 mutations in eighty-one unrelated probands with Marfan syndrome and other fibrillinopathies.

Arbustini E, Grasso M, Ansaldi S, Malattia C, Pilotto A, Porcu E, Disabella E, Marziliano N, Pisani A, Lanzarini L, Mannarino S, Larizza D, Mosconi M, Antoniazzi E, Zoia MC, Meloni G, Magrassi L, Brega A, Bedeschi MF, Torrente I, Mari F, Tavazzi L.

Hum Mutat. 2005 Nov;26(5):494.

PubMed [citation]

PMID:: 16222657

See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000058836.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (5)

Description

The Pro1424Ala missense variant in the FBN1 gene has previously been identified in at least two individuals with clinical features of Marfan syndrome (Collod-Be roud 1998, Comeglio 2001, Biggin 2004). Furthermore, a different variant at this position (Pro1424Ser) has also been reported in one other individual with clini cal features of Marfan syndrome (Arbustini, 2005). However, the Pro1424Ala varia nt was also detected in 0.05% (4/8592) European American chromosomes from a broa d population screened by the NHLBI Exome Sequencing Project (http://evs.gs.washi ngton.edu; dbSNP rs201273753). Computational analyses (biochemical amino acid pr operties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong su pport for or against an impact to the protein. While the Pro1424Ala variant has been seen in several individuals with clinical features of Marfan syndrome, it h as also been seen at a low frequency in the general population. In summary, addi tional information is needed to assess the clinical significance of this variant .

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695537.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (14)

Description

Variant summary: FBN1 c.4270C>G (p.Pro1424Ala) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251532 control chromosomes. The observed variant frequency is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in FBN1 causing Marfan Syndrome phenotype (0.00011), strongly suggesting that the variant is benign. c.4270C>G has been reported in the literature in individuals affected with features of or undergoing testing for Marfan Syndrome/familial thoracic aortic aneurysms and dissections. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11748851, 14695540, 12938084, 17657824, 17627385, 19161152, 9399842, 19293843, 23506379, 24941995, 25637381, 27153395, 26787436). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=11, B/LB, n=2). Based on the evidence outlined above, the variant was classified as likely benign.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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