chrX-136207946-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001159702.3(FHL1):c.486C>G(p.Cys162Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C162C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000088 ( 0 hom., 1 hem., cov: 23)

Failed GnomAD Quality Control

Consequence

FHL1
NM_001159702.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 1.12

Publications

0 publications found

Variant links:

Genes affected

FHL1 (HGNC:3702): (four and a half LIM domains 1) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]

FHL1 Gene-Disease associations (from GenCC):

X-linked myopathy with postural muscle atrophy
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
myopathy, reducing body, X-linked, early-onset, severe
Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
reducing body myopathy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked Emery-Dreifuss muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked scapuloperoneal muscular dystrophy
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

FHL1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3 link	c.486C>G	p.Cys162Trp	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1	Q13642-2
FHL1	NM_001159699.2 link	c.534C>G	p.Cys178Trp	missense_variant	Exon 4 of 6	ENST00000370683.6	NP_001153171.1	Q13642-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8 link	c.486C>G	p.Cys162Trp	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2		Q13642-2
FHL1	ENST00000370683.6 link	c.534C>G	p.Cys178Trp	missense_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1		Q13642-5

Frequencies

GnomAD3 genomes

AF:

0.00000885

AC:

AN:

113040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000885

AC:

AN:

113040

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

35176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31144

American (AMR)

AF:

0.00

AC:

AN:

10799

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3591

South Asian (SAS)

AF:

0.00

AC:

AN:

2766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6253

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53381

Other (OTH)

AF:

0.00

AC:

AN:

1521

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Nov 21, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

X-linked myopathy with postural muscle atrophy

Uncertain:1

Jul 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the FHL1 protein (p.Cys162Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 286484). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

FHL1-related disorder

Uncertain:1

Jul 29, 2021

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The FHL1 c.486C>G (p.Cys162Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest that the variant is rare. The p.Cys162Trp variant lies within the LIM zinc-binding 3 domain of the protein and affects one of the conserved cysteine residues critical for binding zinc ions (Wei et al. 2020). Based on the available evidence, the p.Cys162Trp variant is classified as a variant of uncertain significance for FHL1-related disorders. -

Cardiovascular phenotype

Uncertain:1

Jul 11, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C162W variant (also known as c.486C>G), located in coding exon 3 of the FHL1 gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.67

BayesDel_noAF

Pathogenic

0.73

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.82

.;D;.;.;T;.;T;.;T;.;.;T;.;D;.;.;T;D;.

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

.;D;.;D;D;.;.;.;D;.;D;D;D;.;D;D;D;D;.

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.4

H;H;H;H;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H

PhyloP100

1.1

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-10

.;D;D;.;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0050

.;D;D;.;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Polyphen

1.0

.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.

Vest4

0.96

MutPred

0.88

Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);.;.;.;Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);

MVP

1.0

MPC

1.6

ClinPred

1.0

GERP RS

0.41

Varity_R

0.99

Mutation Taster

=5/95

disease causing

(source)

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

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chrX-136207946-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over