VCV000281831.15 - ClinVar

NM_001079802.2(FKTN):c.706A>G (p.Met236Val)

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.

(5)

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_001079802.2(FKTN):c.706A>G (p.Met236Val)

Variation ID: 281831 Accession: VCV000281831.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q31.2 9: 105607877 (GRCh38) [ NCBI UCSC ] 9: 108370158 (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	Mar 8, 2017	Feb 4, 2024	Aug 30, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079802.2:c.706A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073270.1:p.Met236Val	missense
NM_001198963.2:c.706A>G	NP_001185892.1:p.Met236Val	missense
NM_001351496.2:c.706A>G	NP_001338425.1:p.Met236Val	missense
NM_001351497.2:c.637A>G	NP_001338426.1:p.Met213Val	missense
NM_001351498.2:c.706A>G	NP_001338427.1:p.Met236Val	missense
NM_001351499.2:c.310A>G	NP_001338428.1:p.Met104Val	missense
NM_001351500.2:c.310A>G	NP_001338429.1:p.Met104Val	missense
NM_001351501.2:c.310A>G	NP_001338430.1:p.Met104Val	missense
NM_001351502.2:c.310A>G	NP_001338431.1:p.Met104Val	missense
NM_006731.2:c.706A>G	NP_006722.2:p.Met236Val	missense
NR_147213.2:n.921A>G		non-coding transcript variant
NR_147214.2:n.829A>G		non-coding transcript variant
NC_000009.12:g.105607877A>G
NC_000009.11:g.108370158A>G
NG_008754.1:g.54748A>G
LRG_434:g.54748A>G
LRG_434t1:c.706A>G	LRG_434p1:p.Met236Val
LRG_434t2:c.706A>G	LRG_434p2:p.Met236Val

... more HGVS ... less HGVS

Protein change

M236V, M104V, M213V

Other names

Canonical SPDI

NC_000009.12:105607876:A: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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Links

ClinGen: CA10603977 dbSNP: rs886042241 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.
FKTN		-	-	GRCh38 GRCh37	1016	1066

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	Aug 30, 2022	RCV000724974.8
Walker-Warburg congenital muscular dystrophy	Uncertain significance (2)	criteria provided, single submitter	Aug 11, 2022	RCV001239545.8

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 (Jul 20, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000332832.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKTN Number of individuals with the variant: 1 Sex: mixed
Uncertain significance (Sep 21, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000536300.4 First in ClinVar: Mar 08, 2017 Last updated: Apr 17, 2019	Comment: A variant of uncertain significance has been identified in the FKTN gene. The M236V variant has not been published as pathogenic or been reported as … (more) A variant of uncertain significance has been identified in the FKTN gene. The M236V variant has not been published as pathogenic or been reported as benign to our knowledge. The M236V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, the M236V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less)
Uncertain significance (Aug 11, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Walker-Warburg congenital muscular dystrophy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001412424.3 First in ClinVar: Jul 16, 2020 Last updated: Feb 07, 2023	Comment: This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 236 of the FKTN protein (p.Met236Val). … (more) This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 236 of the FKTN protein (p.Met236Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 281831). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 (Aug 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003832693.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Jun 01, 2020)	no assertion criteria provided Method: clinical testing	Walker-Warburg congenital muscular dystrophy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002079593.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

A variant of uncertain significance has been identified in the FKTN gene. The M236V variant has not been published as pathogenic or been reported as benign to our knowledge. The M236V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). However, the M236V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

Comment:

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 236 of the FKTN protein (p.Met236Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FKTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 281831). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKTN	-	-	-	-

Text-mined citations for rs886042241 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001079802.2(FKTN):c.706A>G (p.Met236Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs886042241 ...