NM_001458.5(FLNC):c.6689G>A (p.Arg2230His) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Sep 7, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000687144.4

Allele description [Variation Report for NM_001458.5(FLNC):c.6689G>A (p.Arg2230His)]

NM_001458.5(FLNC):c.6689G>A (p.Arg2230His)

Genes:
FLNC-AS1:FLNC antisense RNA 1 [Gene - HGNC]
FLNC:filamin C [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
7q32.1
Genomic location:
Preferred name:
NM_001458.5(FLNC):c.6689G>A (p.Arg2230His)
HGVS:
  • NC_000007.14:g.128854178G>A
  • NG_011807.1:g.28750G>A
  • NM_001127487.2:c.6590G>A
  • NM_001458.4:c.6689G>A
  • NM_001458.5:c.6689G>AMANE SELECT
  • NP_001120959.1:p.Arg2197His
  • NP_001449.3:p.Arg2230His
  • NP_001449.3:p.Arg2230His
  • LRG_870t1:c.6689G>A
  • LRG_870:g.28750G>A
  • LRG_870p1:p.Arg2230His
  • NC_000007.13:g.128494232G>A
Protein change:
R2197H
Links:
dbSNP: rs376035195
NCBI 1000 Genomes Browser:
rs376035195
Molecular consequence:
  • NM_001127487.2:c.6590G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001458.4:c.6689G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001458.5:c.6689G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Myofibrillar myopathy, filamin C-related (MFM5)
Synonyms:
FILAMINOPATHY, AUTOSOMAL DOMINANT; MYOPATHY, MYOFIBRILLAR, 5; Filaminopathy (type)
Identifiers:
MONDO: MONDO:0012289; MedGen: C1836050; OMIM: 609524
Name:
Myopathy, distal, 4 (MPD4)
Synonyms:
WILLIAMS DISTAL MYOPATHY
Identifiers:
MONDO: MONDO:0013550; MedGen: C3279722; Orphanet: 63273; OMIM: 614065
Name:
Cardiomyopathy, familial hypertrophic, 26 (CMH26)
Identifiers:
MONDO: MONDO:0014883; MedGen: C4310749; Orphanet: 75249; OMIM: 617047
Name:
Dilated Cardiomyopathy, Dominant
Identifiers:
MedGen: CN239310

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000814696Invitaecriteria provided, single submitter
Uncertain significance
(Sep 7, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000814696.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

This sequence change replaces arginine with histidine at codon 2230 of the FLNC protein (p.Arg2230His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs376035195, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 567146). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 6, 2021

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