VCV000286484.19 - ClinVar

NM_001159699.2(FHL1):c.534C>G (p.Cys178Trp)

Germline

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.

(6)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001159699.2(FHL1):c.534C>G (p.Cys178Trp)

Variation ID: 286484 Accession: VCV000286484.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq26.3 X: 136207946 (GRCh38) [ NCBI UCSC ] X: 135290105 (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	Dec 6, 2016	May 1, 2024	Nov 17, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001159699.2:c.534C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001153171.1:p.Cys178Trp	missense
NM_001159702.3:c.486C>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001153174.1:p.Cys162Trp	missense
NM_001159700.2:c.486C>G	NP_001153172.1:p.Cys162Trp	missense
NM_001159701.2:c.573C>G	NP_001153173.1:p.Cys191Trp	missense
NM_001159703.2:c.486C>G	NP_001153175.1:p.Cys162Trp	missense
NM_001159704.1:c.486C>G	NP_001153176.1:p.Cys162Trp	missense
NM_001167819.1:c.486C>G	NP_001161291.1:p.Cys162Trp	missense
NM_001330659.2:c.534C>G	NP_001317588.1:p.Cys178Trp	missense
NM_001369326.1:c.486C>G	NP_001356255.1:p.Cys162Trp	missense
NM_001369327.2:c.486C>G	NP_001356256.1:p.Cys162Trp	missense
NM_001369328.1:c.486C>G	NP_001356257.1:p.Cys162Trp	missense
NM_001369329.1:c.486C>G	NP_001356258.1:p.Cys162Trp	missense
NM_001369330.1:c.486C>G	NP_001356259.1:p.Cys162Trp	missense
NM_001369331.1:c.486C>G	NP_001356260.1:p.Cys162Trp	missense
NM_001449.5:c.486C>G	NP_001440.2:p.Cys162Trp	missense
NR_027621.2:n.897C>G		non-coding transcript variant
NC_000023.11:g.136207946C>G
NC_000023.10:g.135290105C>G
NG_015895.1:g.65547C>G
LRG_739:g.65547C>G
LRG_739t1:c.534C>G	LRG_739p1:p.Cys178Trp
LRG_739t2:c.486C>G	LRG_739p2:p.Cys162Trp

... more HGVS ... less HGVS

Protein change

C162W, C178W, C191W

Other names

Canonical SPDI

NC_000023.11:136207945:C:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA10605481 dbSNP: rs377693754 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	495	670

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.
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Nov 21, 2022	RCV000292612.9
X-linked myopathy with postural muscle atrophy	Uncertain significance (1)	criteria provided, single submitter	Nov 17, 2023	RCV000537056.9
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Jul 11, 2022	RCV002338847.2
FHL1-related disorder	Uncertain significance (1)	criteria provided, single submitter	Jul 29, 2021	RCV004547710.1

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.	More information 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.
Uncertain significance (Mar 01, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000339927.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FHL1 Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Jul 29, 2021)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	FHL1-related disorders Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV002034758.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021	Publications: PubMed (1) PubMed: 32587768 Comment: The FHL1 c.486C>G (p.Cys162Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications … (more) The FHL1 c.486C>G (p.Cys162Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest that the variant is rare. The p.Cys162Trp variant lies within the LIM zinc-binding 3 domain of the protein and affects one of the conserved cysteine residues critical for binding zinc ions (Wei et al. 2020). Based on the available evidence, the p.Cys162Trp variant is classified as a variant of uncertain significance for FHL1-related disorders. (less)
Uncertain significance (Jun 22, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001992340.3 First in ClinVar: Nov 06, 2021 Last updated: Mar 04, 2023	Comment: Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); In silico analysis supports that this … (more) Has not been previously published as pathogenic or benign to our knowledge; Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function (less)
Uncertain significance (Nov 21, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003832593.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Nov 17, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	X-linked myopathy with postural muscle atrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000647047.6 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 28492532 Comment: This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the FHL1 … (more) This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the FHL1 protein (p.Cys162Trp). 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: 286484). 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. 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. (less)
Uncertain significance (Jul 11, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002634931.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The p.C162W variant (also known as c.486C>G), located in coding exon 3 of the FHL1 gene, results from a C to G substitution at nucleotide … (more) The p.C162W variant (also known as c.486C>G), located in coding exon 3 of the FHL1 gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)

Comment:

The FHL1 c.486C>G (p.Cys162Trp) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggest that the variant is rare. The p.Cys162Trp variant lies within the LIM zinc-binding 3 domain of the protein and affects one of the conserved cysteine residues critical for binding zinc ions (Wei et al. 2020). Based on the available evidence, the p.Cys162Trp variant is classified as a variant of uncertain significance for FHL1-related disorders.

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the FHL1 protein (p.Cys162Trp). 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: 286484). 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. 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.

Comment:

The p.C162W variant (also known as c.486C>G), located in coding exon 3 of the FHL1 gene, results from a C to G substitution at nucleotide position 486. The cysteine at codon 162 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Four and a half LIM domains protein 1 can be as a double-edged sword in cancer progression.	Wei X	Cancer biology & medicine	2020	PMID: 32587768
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FHL1	-	-	-	-

Text-mined citations for rs377693754 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_001159699.2(FHL1):c.534C>G (p.Cys178Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377693754 ...