rs377693754

chrX-136207946-C-GchrX-136207946-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001159702.3(FHL1):c.486C>G(p.Cys162Trp) 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. C162C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 1 hem., cov: 23)
  • Failed GnomAD Quality Control
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 1.12

Genes affected

FHL1 (HGNC:3702): (four and a half LIM domains 1) This gene encodes a member of the four-and-a-half-LIM-only protein family. Family members contain two highly conserved, tandemly arranged, zinc finger domains with four highly conserved cysteines binding a zinc atom in each zinc finger. Expression of these family members occurs in a cell- and tissue-specific mode and these proteins are involved in many cellular processes. Mutations in this gene have been found in patients with Emery-Dreifuss muscular dystrophy. Multiple alternately spliced transcript variants which encode different protein isoforms have been described.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FHL1	NM_001159702.3	c.486C>G	p.Cys162Trp	missense_variant	5/8	ENST00000394155.8
FHL1	NM_001159699.2	c.534C>G	p.Cys178Trp	missense_variant	4/6	ENST00000370683.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FHL1	ENST00000394155.8	c.486C>G	p.Cys162Trp	missense_variant	5/8	5	NM_001159702.3
FHL1	ENST00000370683.6	c.534C>G	p.Cys178Trp	missense_variant	4/6	1	NM_001159699.2	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 113040 Hom.: 0 Cov.: 23 AF XY: 0.0000284 AC XY: 1 AN XY: 35176 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000187

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000885 AC: 1 AN: 113040 Hom.: 0 Cov.: 23 AF XY: 0.0000284 AC XY: 1 AN XY: 35176

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000187

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2022	Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -

FHL1-related disorders Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 29, 2021

The FHL1 c.486C>G (p.Cys162Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest that the variant is rare. The p.Cys162Trp variant lies within the LIM zinc-binding 3 domain of the protein and affects one of the conserved cysteine residues critical for binding zinc ions (Wei et al. 2020). Based on the available evidence, the p.Cys162Trp variant is classified as a variant of uncertain significance for FHL1-related disorders. -

X-linked myopathy with postural muscle atrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the FHL1 protein (p.Cys162Trp). This variant is not present in population databases (gnomAD no frequency). 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: 286484). 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. 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. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2022

The p.C162W variant (also known as c.486C>G), located in coding exon 3 of the FHL1 gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.73
Cadd	Uncertain	25
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;.;H;.;H;.;H;H;.;.;H;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.
Vest4		0.96
MutPred		0.88		Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);.;.;.;Gain of MoRF binding (P = 0.0375);Gain of MoRF binding (P = 0.0375);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		0.41
Varity_R		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs377693754; hg19: chrX-135290105;