Submissions for variant NM_006329.4(FBLN5):c.1117C>T (p.Arg373Cys)

dbSNP: rs864309526

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756132	SCV000883852	likely pathogenic	not provided	2017-11-09	criteria provided, single submitter	clinical testing	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.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV001843302	SCV000886431	likely pathogenic	Charcot-Marie-Tooth disease, demyelinating, IIA 1H	2018-10-23	criteria provided, single submitter	research
GeneDx	RCV000756132	SCV001788378	likely pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000756132	SCV002245453	pathogenic	not provided	2023-09-08	criteria provided, single submitter	clinical testing	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FBLN5 protein function. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV001843302	SCV005013290	likely pathogenic	Charcot-Marie-Tooth disease, demyelinating, IIA 1H	2024-04-23	criteria provided, single submitter	clinical testing
OMIM	RCV001843302	SCV000257547	pathogenic	Charcot-Marie-Tooth disease, demyelinating, IIA 1H	2013-07-01	no assertion criteria provided	literature only
Inherited Neuropathy Consortium Ii, University Of Miami	RCV003447124	SCV004174393	uncertain significance	Hereditary sensorimotor neuropathy with hyperelastic skin	2016-01-06	no assertion criteria provided	literature only