rs864309526
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_006329.4(FBLN5):c.1117C>T(p.Arg373Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_006329.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FBLN5 | NM_006329.4 | c.1117C>T | p.Arg373Cys | missense_variant | Exon 10 of 11 | ENST00000342058.9 | NP_006320.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461858Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727234
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease, demyelinating, IIA 1H Pathogenic:3
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not provided Pathogenic:3
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBLN5-related conditions (PMID: 21576112, 23328402, 28332470, 31945625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218358). 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 not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual who was part of a peripheral neuropathy cohort (Auer-Grumbach 2011, Cheng 2017, Laššuthová 2016, and Šafka Brozková 2013). The p.Arg373Cys is also absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 373 is highly conserved considering 11 species up to frog (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FBLN5 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available evidence, the p.Arg373Cys variant is classified as likely pathogenic. -
Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, 32802946, 31945625); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29412171, 23328402, 27549087, 23293578, 24244300, 21576112, 32802946, 31945625, 31589614, 32757322, 28332470) -
Hereditary sensorimotor neuropathy with hyperelastic skin Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at