rs122459149

Variant names:

• chrX-136208578-T-C
• rs122459149
• NM_001159702.3:c.625T>C

Variant summary

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

The NM_001159699.2(FHL1):​c.673T>C​(p.Cys225Arg) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.98

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-136208578-T-C is Pathogenic according to our data. Variant chrX-136208578-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11557.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-136208578-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.625T>C	p.Cys209Arg	missense_variant	Exon 6 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.673T>C	p.Cys225Arg	missense_variant	Exon 5 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.625T>C	p.Cys209Arg	missense_variant	Exon 6 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.673T>C	p.Cys225Arg	missense_variant	Exon 5 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Pathogenic:1

Jun 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 209 of the FHL1 protein (p.Cys209Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Emery-Dreifuss muscular dystrophy (PMID: 19716112). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11557). 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. For these reasons, this variant has been classified as Pathogenic. -

Emery-Dreifuss muscular dystrophy 6 Pathogenic:1

Jan 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;.;.;.;.;D;.;.;D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	.;D;.;.;.;.;D;.;D;D;D;.
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.4	H;H;H;H;H;H;H;H;.;.;.;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-12	.;D;D;.;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;D;D;.;D;D;D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;D;.;.;.;.
Vest4		0.98
MutPred		0.94		Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);.;.;Loss of ubiquitination at K214 (P = 0.043);Loss of ubiquitination at K214 (P = 0.043);
MVP		1.0
MPC		1.9
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs122459149; hg19: chrX-135290737;