chrX-136209946-G-C

Position:

• chrX-136209946-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

The ENST00000370683.6(FHL1):​c.812G>C​(p.Cys271Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000904 in 110,577 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C271W) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 22)
• Consequence: FHL1 ENST00000370683.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:1
• Conservation: PhyloP100: 9.60

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 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-136209946-G-C is Pathogenic according to our data. Variant chrX-136209946-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.39428917). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FHL1	NM_001159702.3	c.964G>C	p.Ala322Pro	missense_variant	8/8	ENST00000394155.8	NP_001153174.1
FHL1	NM_001159699.2	c.812G>C	p.Cys271Ser	missense_variant	6/6	ENST00000370683.6	NP_001153171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FHL1	ENST00000394155.8	c.964G>C	p.Ala322Pro	missense_variant	8/8	5	NM_001159702.3	ENSP00000377710
FHL1	ENST00000370683.6	c.812G>C	p.Cys271Ser	missense_variant	6/6	1	NM_001159699.2	ENSP00000359717	P1

Frequencies

GnomAD3 genomes AF: 0.00000904 AC: 1 AN: 110577 Hom.: 0 Cov.: 22 AF XY: 0.0000305 AC XY: 1 AN XY: 32839

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: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome AF: 0.00000904 AC: 1 AN: 110577 Hom.: 0 Cov.: 22 AF XY: 0.0000305 AC XY: 1 AN XY: 32839

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: 0.0000189

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 21, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29926425, 25246303, 26857240, 25965631, Marco2022[Abstract], 33673806, Borrelli2022[Poster], 36291626, Aohara2022[CaseReport]) -

X-linked myopathy with postural muscle atrophy Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 255 of the FHL1 protein (p.Cys255Ser). 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, hypertrophic cardiomyopathy, and distal myopathy (PMID: 25246303, 26857240). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 222635). 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. -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Likely pathogenic and reported on 01-11-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Primary familial hypertrophic cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 06, 2015

- -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2023

The p.C255S variant (also known as c.764G>C), located in coding exon 5 of the FHL1 gene, results from a G to C substitution at nucleotide position 764. The cysteine at codon 255 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in individuals affected with FHL1-related disease and has been shown to segregate with disease in family members (D'Arcy C et al. J Child Neurol, 2015 Aug;30:1211-7; San Román I et al. Clin Genet, 2016 Aug;90:171-6; Hathaway J et al. BMC Cardiovasc Disord, 2021 Mar;21:126; Mazzaccara C et al. Biomolecules, 2022 Oct;12:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is expected to be causative of FHL1-related myopathy with hypertrophy; however, its clinical significance for FHL1-related reducing body myopathy is unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.80	T;T;.;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Benign	0.39	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	0.96	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.12	N;.;N;N
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;.;D;T
Sift4G	Pathogenic	0.0	.;D;.;D
Polyphen		0.97	D;P;D;P
Vest4		0.18
MutPred		0.24		Gain of catalytic residue at A322 (P = 0.0028);.;Gain of catalytic residue at A322 (P = 0.0028);.;
MVP		0.99
MPC		1.5
ClinPred		0.78	D
GERP RS		4.7
Varity_R		0.45

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: rs869025431; hg19: chrX-135292105;