NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp) AND X-linked myopathy with postural muscle atrophy

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 27, 2026
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000012304.41

Allele description [Variation Report for NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)]

NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)

Gene:

FHL1:four and a half LIM domains 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq26.3

Genomic location:

Preferred name:

NM_001159699.2(FHL1):c.720C>G (p.Cys240Trp)

HGVS:

NC_000023.11:g.136208625C>G
NG_015895.1:g.66226C>G
NM_001159699.2:c.720C>GMANE SELECT
NM_001159700.2:c.672C>G
NM_001159701.2:c.759C>G
NM_001159702.3:c.672C>G
NM_001159703.2:c.501+664C>G
NM_001159704.1:c.672C>G
NM_001167819.1:c.672C>G
NM_001330659.2:c.549+664C>G
NM_001369326.1:c.672C>G
NM_001369327.2:c.672C>G
NM_001369328.1:c.672C>G
NM_001369329.1:c.672C>G
NM_001369330.1:c.672C>G
NM_001369331.1:c.672C>G
NM_001449.5:c.672C>G
NP_001153171.1:p.Cys240Trp
NP_001153172.1:p.Cys224Trp
NP_001153173.1:p.Cys253Trp
NP_001153174.1:p.Cys224Trp
NP_001153176.1:p.Cys224Trp
NP_001161291.1:p.Cys224Trp
NP_001356255.1:p.Cys224Trp
NP_001356256.1:p.Cys224Trp
NP_001356257.1:p.Cys224Trp
NP_001356258.1:p.Cys224Trp
NP_001356259.1:p.Cys224Trp
NP_001356260.1:p.Cys224Trp
NP_001440.2:p.Cys224Trp
LRG_739t1:c.720C>G
LRG_739t2:c.672C>G
LRG_739:g.66226C>G
LRG_739p1:p.Cys240Trp
LRG_739p2:p.Cys224Trp
NC_000023.10:g.135290784C>G
NM_001159702.2:c.672C>G
NR_027621.2:n.1083C>G
Q13642:p.Cys224Trp

Protein change:

C224W; CYS224TRP

Links:

UniProtKB: Q13642#VAR_042605; OMIM: 300163.0002; dbSNP: rs122458141

Molecular consequence:

NM_001159703.2:c.501+664C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001330659.2:c.549+664C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001159699.2:c.720C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001159700.2:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001159701.2:c.759C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001159702.3:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001159704.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001167819.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369326.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369327.2:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369328.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369329.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369330.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369331.1:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001449.5:c.672C>G - missense variant - [Sequence Ontology: SO:0001583]
NR_027621.2:n.1083C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: X-linked myopathy with postural muscle atrophy
Synonyms:: FHL1-Related Emery-Dreifuss Muscular Dystrophy, X-Linked
Identifiers:: MONDO: MONDO:0010401; MedGen: C2678055; OMIM: 300696

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000032538	OMIM	no assertion criteria provided	Pathogenic (Aug 18, 2009)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19687455, 18179888
SCV001440683	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001588249	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2026)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18179888, 19687455, 22923418, 24634512, 28492532
SCV006323808	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Pathogenic (Jun 11, 2024)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1.

Windpassinger C, Schoser B, Straub V, Hochmeister S, Noor A, Lohberger B, Farra N, Petek E, Schwarzbraun T, Ofner L, Löscher WN, Wagner K, Lochmüller H, Vincent JB, Quasthoff S.

Am J Hum Genet. 2008 Jan;82(1):88-99. doi: 10.1016/j.ajhg.2007.09.004.

PubMed [citation]

PMID:: 18179888
PMCID:: PMC2253986

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000032538.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In an extensive Austrian family in which males in 5 generations had a novel form of myopathy referred to as X-linked myopathy with postural muscle atrophy and generalized hypertrophy (XMPMA; 300696), Windpassinger et al. (2008) detected a 672C-G transversion in the FHL1 gene that resulted in a cys224-to-trp (C224W) substitution in the fourth LIM domain of isoform A and in the nuclear localization signal of isoform B. Patients had muscle hypertrophy in the early stages, followed by postural muscle weakness and atrophy, increased serum creatine kinase, bent spine, and cardiomyopathy. The C224W mutation was predicted to disrupt the zinc-binding properties of FHL1A and to impair shuttling between nucleus and cytoplasm of FHL1B. Impairment of zinc binding may have reduced protein stability and structure. Isoform C was not affected, which the authors hypothesized may have resulted in the relatively mild phenotype; no females were affected.

Schoser et al. (2009) reported 3 additional unrelated German families with XMPMA associated with the C224W mutation in the FHL1 gene. A fourth patient, later found to be distantly related to the Austrian family reported by Windpassinger et al. (2008), was also identified. The phenotype was similar to that reported by Windpassinger et al. (2008). The mutation is predicted to disrupt the fourth LIM domain.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440683.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001588249.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 224 of the FHL1 protein (p.Cys224Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with myopathy with postural muscle atrophy and generalized hypertrophy (PMID: 18179888, 19687455, 22923418). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11548). 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. Experimental studies have shown that this missense change affects FHL1 function (PMID: 24634512). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV006323808.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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