rs370406338

Variant names:

• chr7-128838327-A-G
• rs370406338
• NM_001458.5:c.1108A>G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001458.5(FLNC):​c.1108A>G​(p.Met370Val) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,613,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: FLNC NM_001458.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.05

Genes affected

FLNC (HGNC:3756): (filamin C) This gene encodes one of three related filamin genes, specifically gamma filamin. These filamin proteins crosslink actin filaments into orthogonal networks in cortical cytoplasm and participate in the anchoring of membrane proteins for the actin cytoskeleton. Three functional domains exist in filamin: an N-terminal filamentous actin-binding domain, a C-terminal self-association domain, and a membrane glycoprotein-binding domain. Mutations in this gene are a cause of cardiopathy. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21802261).
• BP6: Variant 7-128838327-A-G is Benign according to our data. Variant chr7-128838327-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 572629.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}. Variant chr7-128838327-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLNC	NM_001458.5	c.1108A>G	p.Met370Val	missense_variant	Exon 7 of 48	ENST00000325888.13	NP_001449.3
FLNC	NM_001127487.2	c.1108A>G	p.Met370Val	missense_variant	Exon 7 of 47		NP_001120959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLNC	ENST00000325888.13	c.1108A>G	p.Met370Val	missense_variant	Exon 7 of 48	1	NM_001458.5	ENSP00000327145.8
FLNC	ENST00000346177.6	c.1108A>G	p.Met370Val	missense_variant	Exon 7 of 47	1		ENSP00000344002.6

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152216 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000104 AC: 26 AN: 249566 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135396

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000312 AC: 456 AN: 1461770 Hom.: 0 Cov.: 34 AF XY: 0.000319 AC XY: 232 AN XY: 727188

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000389

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000118 AC: 1

ExAC AF: 0.0000578 AC: 7

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Aug 14, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FLNC: BP4 -

Primary dilated cardiomyopathy Uncertain:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene. Loss of function is the established mechanism of disease for variants in dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy (MIM#617047) and myofibrillar myopathy (MIM#609524). In distal myopathy (MIM#614065), NMD-predicted variants cause a loss of function, however missense variants have been shown to result in a toxic gain of function (PMID:32112656). (I) 0107 - This gene is associated with autosomal dominant disease. Variants located throughout the gene that are predicted to result in nonsense-mediated decay (NMD) are enriched in dilated cardiomyopathy, whereas missense variants in the ROD2 domain are enriched in hypertrophic cardiomyopathy and restrictive cardiomyopathy (MIM#617047). Additionally, myofibrillar myopathy (MIM#609524) is known to result from either missense variants in the ROD2 domain or truncating variants in the Ig-like domain 24, while missense variants in the actin-binding domain and NMD-predicted variants located in the Ig-like domain 15 and have been reported for distal myopathy (MIM#614065) (PMID:32112656). (I) 0200 - Variant is predicted to result in a missense amino acid change from methionine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (31 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated filamin domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported once as VUS in ClinVar without clear phenotype and also has been seen in a control subject in a HCM study (PMID: 28356264). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Cardiovascular phenotype Uncertain:1

Jan 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.M370V variant (also known as c.1108A>G), located in coding exon 7 of the FLNC gene, results from an A to G substitution at nucleotide position 1108. The methionine at codon 370 is replaced by valine, an amino acid with highly similar properties. This variant has been reported in frontotemporal dementia cohorts and in one control individual from a hypertrophic cardiomyopathy study; however, details of cardiovascular history were limited for these individuals (Janssens J et al. Acta Neuropathol Commun, 2015 Nov;3:68; G&oacute;mez J et al. Circ Cardiovasc Genet, 2017 Apr;10; Blauwendraat C et al. Genet Med, 2018 02;20:240-249). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Myofibrillar myopathy 5;C3279722:Distal myopathy with posterior leg and anterior hand involvement;C4310749:Hypertrophic cardiomyopathy 26;CN239310:Dilated Cardiomyopathy, Dominant Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	0.0095
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.061	T;D
Sift4G	Benign	0.27	T;T
Polyphen		0.033	B;B
Vest4		0.51
MVP		0.46
MPC		0.31
ClinPred		0.11	T
GERP RS		5.5
Varity_R		0.29
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370406338; hg19: chr7-128478381;