rs727504674
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_001318895.3(FHL2):c.512C>T(p.Thr171Met) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,608,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_001318895.3 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152230Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000633 AC: 15AN: 236880Hom.: 0 AF XY: 0.0000391 AC XY: 5AN XY: 127850
GnomAD4 exome AF: 0.000151 AC: 220AN: 1456090Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 104AN XY: 723692
GnomAD4 genome AF: 0.000118 AC: 18AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74380
ClinVar
Submissions by phenotype
not specified Uncertain:1
The Thr171Met variant in FHL2 has not been reported in individuals with cardiomy opathy. Data from large population studies is insufficient to assess the frequen cy of this variant. Threonine (Thr) is not well conserved in evolution and 1 mam malian species carries the variant amino acid (Met), raising the possibility tha t this change may be tolerated. Additional computational analyses (biochemical a mino acid properties, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. Additional information is needed to fully assess the clinic al significance of this variant. -
Primary dilated cardiomyopathy Uncertain:1
This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 171 of the FHL2 protein (p.Thr171Met). This variant is present in population databases (rs727504674, gnomAD 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 25358972). ClinVar contains an entry for this variant (Variation ID: 179156). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt FHL2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects FHL2 function (PMID: 25358972). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at