Submissions for variant NM_001159699.2(FHL1):c.409G>A (p.Val137Ile)

gnomAD frequency: 0.00017  dbSNP: rs139402062

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725586	SCV000337937	uncertain significance	not provided	2015-12-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000725586	SCV000724734	likely benign	not provided	2020-06-30	criteria provided, single submitter	clinical testing
Invitae	RCV001210133	SCV001381604	uncertain significance	X-linked myopathy with postural muscle atrophy	2022-09-28	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 121 of the FHL1 protein (p.Val121Ile). This variant is present in population databases (rs139402062, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. 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: 285074). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002450813	SCV002617496	likely benign	Cardiovascular phenotype	2022-07-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV003897613	SCV004715139	likely benign	FHL1-related condition	2022-11-11	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).