rs1556639151

Positions:

• chrX-136207877-AAGCTT-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001159699.2(FHL1):​c.466_470delAGCTT​(p.Ser156fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: FHL1 NM_001159699.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.12

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]

FHL1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136207877-AAGCTT-A is Pathogenic according to our data. Variant chrX-136207877-AAGCTT-A is described in ClinVar as [Pathogenic]. Clinvar id is 469630.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.418_422delAGCTT	p.Ser140fs	frameshift_variant	5/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.466_470delAGCTT	p.Ser156fs	frameshift_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.418_422delAGCTT	p.Ser140fs	frameshift_variant	5/8	5	NM_001159702.3	ENSP00000377710.2
FHL1	ENST00000370683.6	c.466_470delAGCTT	p.Ser156fs	frameshift_variant	4/6	1	NM_001159699.2	ENSP00000359717.1

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Jul 12, 2022

This variant has not been reported in the literature in individuals affected with FHL1-related conditions. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 469630). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser140Leufs*3) in the FHL1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FHL1 are known to be pathogenic (PMID: 18179888, 19687455, 19716112, 22523091, 24114807). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556639151; hg19: chrX-135290036;