X-136207917-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001159702.3(FHL1):c.457T>C(p.Cys153Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C153F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001159702.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-136207917-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 1404846.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant X-136207917-T-C is Pathogenic according to our data. Variant chrX-136207917-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-136207917-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.457T>C	p.Cys153Arg	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.505T>C	p.Cys169Arg	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.457T>C	p.Cys153Arg	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.505T>C	p.Cys169Arg	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 26, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys153 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23965743). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 11552). This missense change has been observed in individual(s) with clinical features of X-linked dominant FHL1-related disorders (PMID: 18274675; Invitae). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 153 of the FHL1 protein (p.Cys153Arg). -

Myopathy, reducing body, X-linked, childhood-onset Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

Abnormality of the musculature Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
Cadd	Pathogenic	28
Dann	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;.;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.0060	D;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		0.98
MutPred		0.77		Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);.;.;.;Loss of ubiquitination at K157 (P = 0.0477);Loss of ubiquitination at K157 (P = 0.0477);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.99

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: rs122458144; hg19: chrX-135290076;