rs267606812

Positions:

• chrX-136207828-A-G
• chrX-136207828-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001159702.3(FHL1):​c.368A>G​(p.His123Arg) variant causes a missense change involving the alteration of a 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159702.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-136207828-A-G is Pathogenic according to our data. Variant chrX-136207828-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 537353.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.368A>G	p.His123Arg	missense_variant	5/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.416A>G	p.His139Arg	missense_variant	4/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.368A>G	p.His123Arg	missense_variant	5/8	5	NM_001159702.3	ENSP00000377710
FHL1	ENST00000370683.6	c.416A>G	p.His139Arg	missense_variant	4/6	1	NM_001159699.2	ENSP00000359717	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 16, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His123 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18274675, 19181672, 24634512). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 537353). This missense change has been observed in individual(s) with X-linked dominant reducing body myopathy (PMID: 22094483, 31204143; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 123 of the FHL1 protein (p.His123Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	.;D;.;D;.;D;D;D;.;.;D;.;D;.;.;D;.;D;D;.;.;.;D;D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D;.;D;D;D;D;D;D;.;.;.;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;.;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.8	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.017	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.96
MutPred		0.96		Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);.;.;.;Loss of catalytic residue at W122 (P = 0.1277);Loss of catalytic residue at W122 (P = 0.1277);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.98

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: rs267606812; hg19: chrX-135289987;