Submissions for variant NM_001159699.2(FHL1):c.812G>C (p.Cys271Ser)

gnomAD frequency: 0.00001  dbSNP: rs869025431

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208197	SCV000263935	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000822468	SCV000963270	pathogenic	X-linked myopathy with postural muscle atrophy	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 255 of the FHL1 protein (p.Cys255Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy, hypertrophic cardiomyopathy, and distal myopathy (PMID: 25246303, 26857240). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222635). 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. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000263325	SCV001774078	likely pathogenic	not provided	2023-12-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29926425, 25246303, 26857240, 25965631, Marco2022[Abstract], 33673806, Borrelli2022[Poster], 36291626, Aohara2022[CaseReport])
Ambry Genetics	RCV004020556	SCV005017556	likely pathogenic	Cardiovascular phenotype	2023-11-20	criteria provided, single submitter	clinical testing	The p.C255S variant (also known as c.764G>C), located in coding exon 5 of the FHL1 gene, results from a G to C substitution at nucleotide position 764. The cysteine at codon 255 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in individuals affected with FHL1-related disease and has been shown to segregate with disease in family members (D'Arcy C et al. J Child Neurol, 2015 Aug;30:1211-7; San Román I et al. Clin Genet, 2016 Aug;90:171-6; Hathaway J et al. BMC Cardiovasc Disord, 2021 Mar;21:126; Mazzaccara C et al. Biomolecules, 2022 Oct;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of FHL1-related myopathy with hypertrophy; however, its clinical significance for FHL1-related reducing body myopathy is unclear.
Eurofins Ntd Llc (ga)	RCV000263325	SCV000338505	uncertain significance	not provided	2016-01-22	flagged submission	clinical testing
GenomeConnect, ClinGen	RCV000822468	SCV001423261	not provided	X-linked myopathy with postural muscle atrophy		no assertion provided	phenotyping only	Variant interpretted as Likely pathogenic and reported on 01-11-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.