VCV000851689.10 - ClinVar

NM_001159699.2(FHL1):c.736+2T>G

Germline

Classification

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

Pathogenic
Pathogenic (1)

This classification is based on the single submission received

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

Variant Details

Identifiers

NM_001159699.2(FHL1):c.736+2T>G

Variation ID: 851689 Accession: VCV000851689.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq26.3 X: 136208643 (GRCh38) [ NCBI UCSC ] X: 135290802 (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	Dec 10, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001159699.2:c.736+2T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001159702.3:c.688+2T>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001159700.2:c.688+2T>G		splice donor
NM_001159701.2:c.775+2T>G		splice donor
NM_001159703.2:c.501+682T>G		intron variant
NM_001159704.1:c.688+2T>G		splice donor
NM_001167819.1:c.688+2T>G		splice donor
NM_001330659.2:c.549+682T>G		intron variant
NM_001369326.1:c.688+2T>G		splice donor
NM_001369327.2:c.688+2T>G		splice donor
NM_001369328.1:c.688+2T>G		splice donor
NM_001369329.1:c.688+2T>G		splice donor
NM_001369330.1:c.688+2T>G		splice donor
NM_001369331.1:c.688+2T>G		splice donor
NM_001449.5:c.688+2T>G		splice donor
NC_000023.11:g.136208643T>G
NC_000023.10:g.135290802T>G
NG_015895.1:g.66244T>G
LRG_739:g.66244T>G
LRG_739t1:c.736+2T>G
LRG_739t2:c.688+2T>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:136208642:T:G

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: CA414609125 dbSNP: rs2073916521 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	695	880

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	Dec 10, 2024	RCV001056132.10

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 (Dec 10, 2024) 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: SCV001220553.7 First in ClinVar: Apr 15, 2020 Last updated: Feb 15, 2026	Publications: PubMed (4) PubMed: 17576681‚ 19716112‚ 22523091‚ 9536098 Comment: show This sequence change affects a donor splice site in intron 6 of the FHL1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). 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: 851689). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the FHL1 protein in which other variant(s) (p.Cys276Tyr) have been determined to be pathogenic (PMID: 19716112, 22523091; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (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:

This sequence change affects a donor splice site in intron 6 of the FHL1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). 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: 851689). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the FHL1 protein in which other variant(s) (p.Cys276Tyr) have been determined to be pathogenic (PMID: 19716112, 22523091; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs2073916521 ...

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