VCV000093517.49 - ClinVar

NM_001079802.2(FKTN):c.166C>T (p.Arg56Cys)

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.

(17)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(11)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001079802.2(FKTN):c.166C>T (p.Arg56Cys)

Variation ID: 93517 Accession: VCV000093517.49

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q31.2 9: 105601145 (GRCh38) [ NCBI UCSC ] 9: 108363426 (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 6, 2014	May 1, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079802.2:c.166C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073270.1:p.Arg56Cys	missense
NM_001198963.2:c.166C>T	NP_001185892.1:p.Arg56Cys	missense
NM_001351496.2:c.166C>T	NP_001338425.1:p.Arg56Cys	missense
NM_001351497.2:c.97C>T	NP_001338426.1:p.Arg33Cys	missense
NM_001351498.2:c.166C>T	NP_001338427.1:p.Arg56Cys	missense
NM_001351499.2:c.-349C>T		5 prime UTR
NM_001351500.2:c.-349C>T		5 prime UTR
NM_001351501.2:c.-349C>T		5 prime UTR
NM_001351502.2:c.-349C>T		5 prime UTR
NM_006731.2:c.166C>T	NP_006722.2:p.Arg56Cys	missense
NR_147213.2:n.381C>T		non-coding transcript variant
NR_147214.2:n.289C>T		non-coding transcript variant
NC_000009.12:g.105601145C>T
NC_000009.11:g.108363426C>T
NG_008754.1:g.48016C>T
LRG_434:g.48016C>T
LRG_434t1:c.166C>T	LRG_434p1:p.Arg56Cys
LRG_434t2:c.166C>T	LRG_434p2:p.Arg56Cys
	O75072:p.Arg56Cys

... more HGVS ... less HGVS

Protein change

R56C, R33C

Other names

p.R56C:CGT>TGT

Canonical SPDI

NC_000009.12:105601144:C:T

Functional
consequence

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

Global minor allele
frequency (GMAF)

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.

0.01038 (T)

Allele frequency

The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.01038

1000 Genomes Project 30x 0.01109

The Genome Aggregation Database (gnomAD), exomes 0.01892

Trans-Omics for Precision Medicine (TOPMed) 0.02053

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02063

The Genome Aggregation Database (gnomAD) 0.02093

Exome Aggregation Consortium (ExAC) 0.02353

Links

UniProtKB: O75072#VAR_061296

dbSNP: rs41277797

ClinGen: CA285421

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 specified	Benign (7)	criteria provided, multiple submitters, no conflicts	Aug 2, 2017	RCV000079431.36
Dilated cardiomyopathy 1X	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000368379.13
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	Benign (2)	criteria provided, multiple submitters, no conflicts	May 18, 2021	RCV000397538.15
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Sep 10, 2015	RCV000619307.11
Walker-Warburg congenital muscular dystrophy	Benign (2)	criteria provided, single submitter	Feb 1, 2024	RCV000466034.20
not provided	Benign (3)	criteria provided, single submitter	Nov 15, 2023	RCV001572926.19
Muscular dystrophy-dystroglycanopathy	Benign (1)	criteria provided, single submitter	May 5, 2023	RCV003993795.1

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.
Benign (Aug 02, 2017)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Athena Diagnostics Accession: SCV000613316.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Publications: PubMed (2) PubMed: 17559086‚ 17878207
Benign (Sep 10, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735023.5 First in ClinVar: Apr 14, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000306353.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 08, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000168563.11 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Nov 18, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111310.8 First in ClinVar: Jan 17, 2014 Last updated: May 03, 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: 2 Sex: mixed
Benign (Mar 03, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000269112.2 First in ClinVar: May 29, 2016 Last updated: Oct 02, 2016	Comment: p.Arg56Cys in exon 5 of FKTN: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (1650/44834) of … (more) p.Arg56Cys in exon 5 of FKTN: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (1650/44834) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41277797). (less) Number of individuals with the variant: 1
Benign (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000476416.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Dilated cardiomyopathy 1X Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000476415.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001653410.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021	Sex: mixed
Benign (Feb 01, 2024)	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: SCV000557840.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024
Benign (Nov 15, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001156898.6 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (May 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Muscular dystrophy-dystroglycanopathy Affected status: no Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812803.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024
Likely benign (-)	no assertion criteria provided Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151168.2 First in ClinVar: May 17, 2014 Last updated: Jul 06, 2014	Comment: Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated … (more) Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. (less)
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001798037.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922894.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001931758.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Jun 04, 2020)	no assertion criteria provided Method: clinical testing	Walker-Warburg congenital muscular dystrophy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002078747.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
click to load more click to collapse

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

p.Arg56Cys in exon 5 of FKTN: This variant is not expected to have clinical sign ificance because it has been identified in 3.7% (1650/44834) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs41277797).

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan.	Godfrey C	Brain : a journal of neurology	2007	PMID: 17878207
Molecular heterogeneity in fetal forms of type II lissencephaly.	Bouchet C	Human mutation	2007	PMID: 17559086
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKTN	-	-	-	-

Text-mined citations for rs41277797 ...

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 08, 2024

ClinVar Genomic variation as it relates to human health

NM_001079802.2(FKTN):c.166C>T (p.Arg56Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs41277797 ...