Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000725941 | SCV007333581 | pathogenic | not provided | 2025-06-03 | criteria provided, single submitter | clinical testing | The FHL1 c.672C>G; p.Cys224Trp variant (rs122458141, ClinVar Variation ID: 11548 ) is reported in the literature in individuals affected with X-linked postural muscle atrophy (XMPMA) and generalized hypertrophy (Binder 2012, Feldkirchner 2013, Schoser 2009). Additionally, this variant was found to segregate with disease in an X-linked recessive manner consistent with XMPMA in six individuals in a single family (Windpassinger 2008). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.798). In vitro functional analyses in C2C12 cells demonstrate similar expression to wildtype FHL1 but showed impaired differentiation (Wilding 2014), additionally patient muscle biopsy showed a marked decrease in protein expression of FHL1 (Windpassinger 2008). Based on available information, this variant is considered to be pathogenic. References: Binder JS et al. Spongious hypertrophic cardiomyopathy in patients with mutations in the four-and-a-half LIM domain 1 gene. Circ Cardiovasc Genet. 2012 Oct 1;5(5):490-502. PMID: 22923418. Feldkirchner S et al. Proteomic characterization of aggregate components in an intrafamilial variable FHL1-associated myopathy. Neuromuscul Disord. 2013 May;23(5):418-26. PMID: 23489660. Schoser B et al. Consequences of mutations within the C terminus of the FHL1 gene. Neurology. 2009 Aug 18;73(7):543-51. PMID: 19687455. Wilding BR et al. FHL1 mutants that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation. J Cell Sci. 2014 May 15;127(Pt 10):2269-81. PMID: 24634512. Windpassinger C et al. An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1. Am J Hum Genet. 2008 Jan;82(1):88-99. PMID: 18179888. |
| Labcorp Genetics |
RCV000012304 | SCV001588249 | pathogenic | X-linked myopathy with postural muscle atrophy | 2026-01-27 | criteria provided, single submitter | clinical testing | 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. |
| Institute of Human Genetics, |
RCV000012304 | SCV001440683 | likely pathogenic | X-linked myopathy with postural muscle atrophy | 2019-01-01 | criteria provided, single submitter | clinical testing | |
| Eurofins Ntd Llc |
RCV000725941 | SCV000340671 | pathogenic | not provided | 2016-03-23 | criteria provided, single submitter | clinical testing | |
| Clinical Genetics Laboratory, |
RCV000012304 | SCV006323808 | pathogenic | X-linked myopathy with postural muscle atrophy | 2024-06-11 | no assertion criteria provided | clinical testing | |
| OMIM | RCV000012304 | SCV000032538 | pathogenic | X-linked myopathy with postural muscle atrophy | 2009-08-18 | no assertion criteria provided | literature only |