X-136209951-G-C

Variant names:

• chrX-136209951-G-C
• rs190006104
• NM_001159699.2:c.817G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_001159699.2(FHL1):​c.817G>C​(p.Val273Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,208,774 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V273M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000035 (0 hom. 14 hem.)
• Consequence: FHL1 NM_001159699.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.21
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• X-linked myopathy with postural muscle atrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myopathy, reducing body, X-linked, early-onset, severe

  Inheritance: XL Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• reducing body myopathy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked scapuloperoneal muscular dystrophy

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_001159699.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.16958019).
• BP6: Variant X-136209951-G-C is Benign according to our data. Variant chrX-136209951-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 838540.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000452 (5/110563) while in subpopulation NFE AF = 0.0000945 (5/52906). AF 95% confidence interval is 0.0000371. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001159699.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	NM_001159699.2	MANE Select	c.817G>C	p.Val273Leu	missense	Exon 6 of 6	NP_001153171.1
	FHL1	NM_001159702.3	MANE Plus Clinical	c.969G>C	p.Pro323Pro	synonymous	Exon 8 of 8	NP_001153174.1
	FHL1	NM_001159701.2		c.856G>C	p.Val286Leu	missense	Exon 6 of 6	NP_001153173.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FHL1	ENST00000370683.6	TSL:1 MANE Select	c.817G>C	p.Val273Leu	missense	Exon 6 of 6	ENSP00000359717.1
	FHL1	ENST00000543669.5	TSL:1	c.769G>C	p.Val257Leu	missense	Exon 6 of 6	ENSP00000443333.1
	FHL1	ENST00000394155.8	TSL:5 MANE Plus Clinical	c.969G>C	p.Pro323Pro	synonymous	Exon 8 of 8	ENSP00000377710.2

Frequencies

GnomAD3 genomes AF: 0.0000452 AC: 5 AN: 110563 Hom.: 0 Cov.: 22

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: 0.0000945

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000436 AC: 8 AN: 183526 AF XY: 0.0000589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.0000346 AC: 38 AN: 1098211 Hom.: 0 Cov.: 33 AF XY: 0.0000385 AC XY: 14 AN XY: 363565

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.000114 AC: 4 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40534

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000392 AC: 33 AN: 842100

Other (OTH) AF: 0.0000217 AC: 1 AN: 46094

GnomAD4 genome AF: 0.0000452 AC: 5 AN: 110563 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32807

African (AFR) AF: 0.00 AC: 0 AN: 30311

American (AMR) AF: 0.00 AC: 0 AN: 10386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3541

South Asian (SAS) AF: 0.00 AC: 0 AN: 2581

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5798

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.0000945 AC: 5 AN: 52906

Other (OTH) AF: 0.00 AC: 0 AN: 1486

Alfa AF: 0.0000868 Hom.: 1

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked myopathy with postural muscle atrophy Uncertain:1

Jan 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 257 of the FHL1 protein (p.Val257Leu). This variant is present in population databases (rs190006104, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FHL1-related conditions. ClinVar contains an entry for this variant (Variation ID: 838540). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Cardiovascular phenotype Uncertain:1

Aug 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V257L variant (also known as c.769G>C), located in coding exon 5 of the FHL1 gene, results from a G to C substitution at nucleotide position 769. The valine at codon 257 is replaced by leucine, an amino acid with highly similar properties. Based on data from gnomAD, the C allele has an overall frequency of <0.01% (8/183526) total alleles studied, with 4 hemizygote(s) observed. The highest observed frequency was 0.01% (3/27431) of Latino alleles. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

not provided Benign:1

Nov 08, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.0035	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.83	T
PhyloP100		1.2
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.34
Sift	Benign	0.88	T
Sift4G	Benign	0.67	T
Vest4		0.16
MutPred		0.38		Loss of catalytic residue at V286 (P = 0.0428)
MVP		0.84
ClinPred		0.018	T
GERP RS		-0.74
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs190006104; hg19: chrX-135292110;