X-136207917-T-C

Variant names:

• chrX-136207917-T-C
• rs122458144
• NM_001159702.3:c.457T>C

Variant summary

Our verdict is Pathogenic. The variant received 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. 12/20 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
• Publications: 5 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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-136207918-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2578367.Status of the report is no_assertion_criteria_provided, 0 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 11552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.457T>C	p.Cys153Arg	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.505T>C	p.Cys169Arg	missense_variant	Exon 4 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.457T>C	p.Cys153Arg	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.505T>C	p.Cys169Arg	missense_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

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

Apr 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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 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

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Pathogenic	0.94	.;D;.;.;D;D;.;D;.;D;.;.;D;.;D;.;.;D;D;.
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;.;.;.;D;.;D;D;D;.;D;D;D;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
PhyloP100		8.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-12	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	.;D;D;.;D;D;.;D;D;D;D;D;D;.;D;D;D;D;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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs122458144; hg19: chrX-135290076;