VCV003255137.1 - ClinVar

NM_004115.4(FGF14):c.256C>T (p.His86Tyr)

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.

(1)

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, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004115.4(FGF14):c.256C>T (p.His86Tyr)

Variation ID: 3255137 Accession: VCV003255137.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q33.1 13: 101875234 (GRCh38) [ NCBI UCSC ] 13: 102527584 (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	Jul 23, 2024	Jul 23, 2024	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004115.4:c.256C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004106.1:p.His86Tyr	missense
NM_001321931.1:c.4C>T	NP_001308860.1:p.His2Tyr	missense
NM_001321932.1:c.67C>T	NP_001308861.1:p.His23Tyr	missense
NM_001321933.1:c.76C>T	NP_001308862.1:p.His26Tyr	missense
NM_001321934.1:c.4C>T	NP_001308863.1:p.His2Tyr	missense
NM_001321935.1:c.4C>T	NP_001308864.1:p.His2Tyr	missense
NM_001321936.1:c.67C>T	NP_001308865.1:p.His23Tyr	missense
NM_001321937.2:c.271C>T	NP_001308866.1:p.His91Tyr	missense
NM_001321938.2:c.76C>T	NP_001308867.1:p.His26Tyr	missense
NM_001321939.2:c.209-6406C>T		intron variant
NM_001321940.1:c.76C>T	NP_001308869.1:p.His26Tyr	missense
NM_001321941.2:c.70C>T	NP_001308870.1:p.His24Tyr	missense
NM_001321942.1:c.4C>T	NP_001308871.1:p.His2Tyr	missense
NM_001321943.1:c.4C>T	NP_001308872.1:p.His2Tyr	missense
NM_001321944.1:c.67C>T	NP_001308873.1:p.His23Tyr	missense
NM_001321945.2:c.154C>T	NP_001308874.1:p.His52Tyr	missense
NM_001321946.2:c.4C>T	NP_001308875.1:p.His2Tyr	missense
NM_001321947.2:c.115C>T	NP_001308876.1:p.His39Tyr	missense
NM_001321948.2:c.154C>T	NP_001308877.1:p.His52Tyr	missense
NM_001321949.1:c.4C>T	NP_001308878.1:p.His2Tyr	missense
NM_001379342.1:c.154C>T	NP_001366271.1:p.His52Tyr	missense
NM_175929.3:c.271C>T	NP_787125.1:p.His91Tyr	missense
NC_000013.11:g.101875234G>A
NC_000013.10:g.102527584G>A
NG_008317.2:g.531541C>T
NG_008317.3:g.532209C>T

... more HGVS ... less HGVS

Protein change

H23Y, H24Y, H26Y, H2Y, H39Y, H52Y, H86Y, H91Y

Other names

Canonical SPDI

NC_000013.11:101875233: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.

Links

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.
FGF14		-	-	GRCh38 GRCh37	181	292

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.
Spinocerebellar ataxia 27A	Uncertain significance (1)	criteria provided, single submitter	Dec 21, 2023	RCV004595320.1

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 (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Spinocerebellar ataxia 27A (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005086491.1 First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024	Publications: PubMed (1) PubMed: 17978045 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with spinocerebellar ataxia 27A (MIM#193003) and spinocerebellar ataxia 27B, late-onset (MIM#620174). Dominant negative has been shown as the mechanism for one missense variant (PMID: 17978045). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibroblast growth factor domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(His86Asn) has been classified as a VUS by a clinical laboratory in ClinVar. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with spinocerebellar ataxia 27A (MIM#193003) and spinocerebellar ataxia 27B, late-onset (MIM#620174). Dominant negative has been shown as the mechanism for one missense variant (PMID: 17978045). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from histidine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated fibroblast growth factor domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. p.(His86Asn) has been classified as a VUS by a clinical laboratory in ClinVar. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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
The FGF14(F145S) mutation disrupts the interaction of FGF14 with voltage-gated Na+ channels and impairs neuronal excitability.	Laezza F	The Journal of neuroscience : the official journal of the Society for Neuroscience	2007	PMID: 17978045

Text-mined citations for this variant ...

Record last updated Aug 04, 2024

ClinVar Genomic variation as it relates to human health

NM_004115.4(FGF14):c.256C>T (p.His86Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...