X-136207826-G-C

Variant names:

• chrX-136207826-G-C
• rs1556639109
• NM_001159702.3:c.366G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001159699.2(FHL1):​c.414G>C​(p.Trp138Cys) 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.00

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant X-136207826-G-C is Pathogenic according to our data. Variant chrX-136207826-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 497823.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.366G>C	p.Trp122Cys	missense_variant	Exon 5 of 8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.414G>C	p.Trp138Cys	missense_variant	Exon 4 of 6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.366G>C	p.Trp122Cys	missense_variant	Exon 5 of 8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.414G>C	p.Trp138Cys	missense_variant	Exon 4 of 6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Jan 12, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 05, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked myopathy with postural muscle atrophy Pathogenic:1

Nov 13, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces tryptophan with cysteine at codon 122 of the FHL1 protein (p.Trp122Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of myofibrillar myopathy (PMID: 20633900). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 497823). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp122 amino acid residue in FHL1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18179901, 25274776). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	.;D;.;T;.;D;D;T;.;.;D;.;D;.;.;D;.;D;D;.;.;.;D;D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	.;D;.;D;D;D;D;D;D;.;.;.;D;.;D;D;D;D;.;.;D;D;D;D;.
M_CAP	Pathogenic	0.91	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	4.4	H;H;H;.;H;.;.;.;.;H;.;H;.;H;H;.;.;.;H;.;.;.;.;.;H
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-12	.;D;D;.;.;D;D;.;.;.;D;D;D;D;D;D;.;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	.;D;D;.;.;D;D;.;.;.;D;D;D;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;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;D;.;.
Vest4		0.94
MutPred		0.90		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);.;.;.;Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		4.4
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: rs1556639109; hg19: chrX-135289985;