Submissions for variant NM_001159699.2(FHL1):c.247C>T (p.Arg83Cys)

gnomAD frequency: 0.00002  dbSNP: rs1379221574

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001366588	SCV001562896	uncertain significance	X-linked myopathy with postural muscle atrophy	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the FHL1 protein (p.Arg67Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1057575). 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 tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV003346523	SCV004051222	uncertain significance	Cardiovascular phenotype	2023-07-23	criteria provided, single submitter	clinical testing	The p.R67C variant (also known as c.199C>T), located in coding exon 2 of the FHL1 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by cysteine, an amino acid with highly dissimilar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.0022% (4/183128) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was 0.0105% (2/19079) of South Asian alleles. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004762128	SCV005373826	uncertain significance	X-linked scapuloperoneal muscular dystrophy	2024-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005057324	SCV005727159	uncertain significance	not specified	2024-11-04	criteria provided, single submitter	clinical testing	Variant summary: FHL1 c.199C>T (p.Arg67Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 183128 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.199C>T in individuals affected with Emery-Dreifuss Muscular Dystrophy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1057575). Based on the evidence outlined above, the variant was classified as uncertain significance.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724303	SCV001958378	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001724303	SCV001963420	uncertain significance	not provided		no assertion criteria provided	clinical testing