VCV000834991.11 - ClinVar

NM_001159699.2(FHL1):c.379+1G>A

Germline

Classification

criteria provided, single submitter. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (1)

1 out of 2 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Functional data are available for this variant

Variant Details

Identifiers

NM_001159699.2(FHL1):c.379+1G>A

Variation ID: 834991 Accession: VCV000834991.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq26.3 X: 136207191 (GRCh38) [ NCBI UCSC ] X: 135289350 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 15, 2020	Feb 15, 2026	Nov 18, 2019

HGVS

Nucleotide	Protein	Molecular consequence
NM_001159699.2:c.379+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001159702.3:c.331+1G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001159700.2:c.331+1G>A		splice donor
NM_001159701.2:c.418+1G>A		splice donor
NM_001159703.2:c.331+1G>A		splice donor
NM_001159704.1:c.331+1G>A		splice donor
NM_001167819.1:c.331+1G>A		splice donor
NM_001330659.2:c.379+1G>A		splice donor
NM_001369326.1:c.331+1G>A		splice donor
NM_001369327.2:c.331+1G>A		splice donor
NM_001369328.1:c.331+1G>A		splice donor
NM_001369329.1:c.331+1G>A		splice donor
NM_001369330.1:c.331+1G>A		splice donor
NM_001369331.1:c.331+1G>A		splice donor
NM_001449.5:c.331+1G>A		splice donor
NC_000023.11:g.136207191G>A
NC_000023.10:g.135289350G>A
NG_015895.1:g.64792G>A
LRG_739:g.64792G>A
LRG_739t1:c.379+1G>A
LRG_739t2:c.331+1G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:136207190:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA414608274 dbSNP: rs2073866799 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FHL1		-	-	GRCh38 GRCh37	674	858

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
X-linked myopathy with postural muscle atrophy	Pathogenic (1)	criteria provided, single submitter	Nov 18, 2019	RCV001035786.10

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 18, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	X-linked myopathy with postural muscle atrophy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001199121.7 First in ClinVar: Apr 15, 2020 Last updated: Feb 15, 2026	Publications: PubMed (6) PubMed: 16199547‚ 18179888‚ 19687455‚ 19716112‚ 22523091‚ 24114807 Comment: show Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FHL1 are known to be pathogenic (PMID: 18179888, 19687455, 19716112, 22523091, 24114807). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of FHL1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the FHL1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in FHL1 are known to be pathogenic (PMID: 18179888, 19687455, 19716112, 22523091, 24114807). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of FHL1-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 4 of the FHL1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Isolated X-linked hypertrophic cardiomyopathy caused by a novel mutation of the four-and-a-half LIM domain 1 gene.	Hartmannova H	Circulation. Cardiovascular genetics	2013	PMID: 24114807
Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.	Friedrich FW	Human molecular genetics	2012	PMID: 22523091
Mutations of the FHL1 gene cause Emery-Dreifuss muscular dystrophy.	Gueneau L	American journal of human genetics	2009	PMID: 19716112
Consequences of mutations within the C terminus of the FHL1 gene.	Schoser B	Neurology	2009	PMID: 19687455
An X-linked myopathy with postural muscle atrophy and generalized hypertrophy, termed XMPMA, is caused by mutations in FHL1.	Windpassinger C	American journal of human genetics	2008	PMID: 18179888
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Submissions - Functional Data

functionally abnormal -- retained intron

assessed by RNAseq

Result:

junction spanning - intron inclusion with mutation (p=0.0076)

Modifies a natural donor site at NC_000023.10:g.135289350 from 3.21 to -15.42 bits. Significant p-values: junction spanning - intron inclusion with mutation (1 reads, p=0.0076). Computations were originally performed using genomic coordinates. This variant was mapped to an appropriate current MANE database designation or, if not present in this source, to the longest relevant transcript in the Biocommons Universal Transcript Archive using the hgvs Python package. The original genomic coordinate was based on GRCh37 and was submitted as an "Alternate designation". Modifications of Figure 2 of PMID:31275557 for ClinVar: a) "strongly corroborating Veridical p-value" refers to "junction-spanning" evidence types; b) add the text "and natural site < 300 nucleotides away?" to "Ri,final > nearest natural site Ri"; c) "Aberrant" and "Likely aberrant" classifications are now both defined as "Functionally abnormal" (analogous to ACMG/AMP reporting); d) "Allele-specific alternative splicing" classification now defined as "Function uncertain" (based on results for similar variants in PMID: 32211018); e) average heterozygosity based-criteria no longer contribute to classification.

Citation: PubMed: 31275557

Dr. Peter K. Rogan Lab, Western University

Accession: SCV006988753.1

Submitted: 2025-10-17

Assay description:

In the sample (TCGA-DJ-A3UK), the counts of splice junction spanning reads and abundance of the transcript adjacent to this mutation were compared with RNASeq data from matched tissues and tumors lacking the same mutation using Veridical (PMID:24741438)

Disease context: Thyroid cancer, nonmedullary, 1
Transcript: NM_001159699.2:c.379+1G>A
Molecular phenotype measured: splicing
Cell line: TCGA-DJ-A3UK
Tissue: Thyroid Carcinoma (THCA)
Collection method: in vitro
Species: human
Number of controls: 530

Text-mined citations for rs2073866799 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 13, 2026