chrX-136207910-C-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_001159702.3(FHL1):c.450C>G(p.Cys150Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C150R) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001159702.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
FHL1 | NM_001159702.3 | c.450C>G | p.Cys150Trp | missense_variant | 5/8 | ENST00000394155.8 | |
FHL1 | NM_001159699.2 | c.498C>G | p.Cys166Trp | missense_variant | 4/6 | ENST00000370683.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
FHL1 | ENST00000394155.8 | c.450C>G | p.Cys150Trp | missense_variant | 5/8 | 5 | NM_001159702.3 | ||
FHL1 | ENST00000370683.6 | c.498C>G | p.Cys166Trp | missense_variant | 4/6 | 1 | NM_001159699.2 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
X-linked myopathy with postural muscle atrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Cys150 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been observed in individuals with FHL1-related conditions (PMID: 19171836, 20571991, 23169582, 25191266), which suggests that this may be a clinically significant amino acid residue. 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. ClinVar contains an entry for this variant (Variation ID: 943902). This missense change has been observed in individual(s) with X-linked dominant FHL1-related conditions (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 150 of the FHL1 protein (p.Cys150Trp). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at