VCV000038385.17 - ClinVar

NM_005247.4(FGF3):c.283C>T (p.Arg95Trp)

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.

(7)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005247.4(FGF3):c.283C>T (p.Arg95Trp)

Variation ID: 38385 Accession: VCV000038385.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11q13.3 11: 69816361 (GRCh38) [ NCBI UCSC ] 11: 69631129 (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 4, 2013	Oct 8, 2024	Sep 13, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_005247.4:c.283C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005238.1:p.Arg95Trp	missense
NC_000011.10:g.69816361G>A
NC_000011.9:g.69631129G>A
NG_009016.1:g.8064C>T
LRG_1303:g.8064C>T
LRG_1303t1:c.283C>T	LRG_1303p1:p.Arg95Trp

... more HGVS ... less HGVS

Protein change

R95W

Other names

Canonical SPDI

NC_000011.10:69816360:G:A

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.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00001

Links

ClinGen: CA343027 dbSNP: rs281860303 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.
FGF3		-	-	GRCh38 GRCh37	87	129

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.
Deafness with labyrinthine aplasia, microtia, and microdontia	not provided (1)	no classification provided	-	RCV000031939.3
not provided	Pathogenic/Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	Sep 13, 2022	RCV000485154.13
FGF3-related disorder	Pathogenic (1)	no assertion criteria provided	Jan 10, 2024	RCV003982855.2

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.
Likely pathogenic (Nov 28, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000858110.1 First in ClinVar: Apr 27, 2017 Last updated: Apr 27, 2017	Publications: PubMed (2) PubMed: 19950373‚ 21306635 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGF3 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Likely pathogenic (Aug 26, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000568861.5 First in ClinVar: Apr 27, 2017 Last updated: Mar 04, 2023	Comment: Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect … (more) Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31336982, 19950373, 21306635, 22993869) (less)
Pathogenic (Sep 13, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002232788.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 19950373‚ 21306635‚ 31336982 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 38385). This variant is also known as c.284C>T. This missense change has been observed in individuals with clinical features of labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome (PMID: 19950373, 21306635, 31336982). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs281860303, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 95 of the FGF3 protein (p.Arg95Trp). (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954247.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001973551.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Jan 10, 2024)	no assertion criteria provided Method: clinical testing	FGF3-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004797611.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The FGF3 c.283C>T variant is predicted to result in the amino acid substitution p.Arg95Trp. This variant was reported in multiple individuals with labyrinthine aplasia, microtia … (more) The FGF3 c.283C>T variant is predicted to result in the amino acid substitution p.Arg95Trp. This variant was reported in multiple individuals with labyrinthine aplasia, microtia and microdontia (LAMM syndrome; OMIM #610706) (Ramsebner et al. 2009. PubMed ID: 19950373; Al Yassin et al. 2019. PubMed ID: 31336982; Riazuddin et al. 2011. PubMed ID: 21306635). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic. (less)
not provided (-)	no classification provided Method: literature only	Deafness with labyrinthine aplasia, microtia, and microdontia Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000054598.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 22993869 BookShelf: NBK100664 BookShelf: NBK100664

Comment:

Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 31336982, 19950373, 21306635, 22993869)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 38385). This variant is also known as c.284C>T. This missense change has been observed in individuals with clinical features of labyrinthine aplasia, microtia, and microdontia (LAMM) syndrome (PMID: 19950373, 21306635, 31336982). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs281860303, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 95 of the FGF3 protein (p.Arg95Trp).

Comment:

The FGF3 c.283C>T variant is predicted to result in the amino acid substitution p.Arg95Trp. This variant was reported in multiple individuals with labyrinthine aplasia, microtia and microdontia (LAMM syndrome; OMIM #610706) (Ramsebner et al. 2009. PubMed ID: 19950373; Al Yassin et al. 2019. PubMed ID: 31336982; Riazuddin et al. 2011. PubMed ID: 21306635). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as pathogenic.

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
Three New Mutations and Mild, Asymmetrical Phenotype in the Highly Distinctive LAMM Syndrome: A Report of Eight Further Cases.	Al Yassin A	Genes	2019	PMID: 31336982
Congenital Deafness with Labyrinthine Aplasia, Microtia, and Microdontia.	Adam MP	-	2019	PMID: 22993869
Variable expressivity of FGF3 mutations associated with deafness and LAMM syndrome.	Riazuddin S	BMC medical genetics	2011	PMID: 21306635
A FGF3 mutation associated with differential inner ear malformation, microtia, and microdontia.	Ramsebner R	The Laryngoscope	2010	PMID: 19950373
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FGF3	-	-	-	-

Text-mined citations for rs281860303 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_005247.4(FGF3):c.283C>T (p.Arg95Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs281860303 ...