VCV000003211.47 - ClinVar

NM_001079802.2(FKTN):c.373G>A (p.Gly125Ser)

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.

(14)

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.

Benign/Likely benign

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.373G>A (p.Gly125Ser)

Variation ID: 3211 Accession: VCV000003211.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q31.2 9: 105604218 (GRCh38) [ NCBI UCSC ] 9: 108366499 (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	May 17, 2014	Sep 29, 2024	Feb 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001079802.2:c.373G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073270.1:p.Gly125Ser	missense
NM_001198963.2:c.373G>A	NP_001185892.1:p.Gly125Ser	missense
NM_001351496.2:c.373G>A	NP_001338425.1:p.Gly125Ser	missense
NM_001351497.2:c.304G>A	NP_001338426.1:p.Gly102Ser	missense
NM_001351498.2:c.373G>A	NP_001338427.1:p.Gly125Ser	missense
NM_001351499.2:c.-24G>A		5 prime UTR
NM_001351500.2:c.-24G>A		5 prime UTR
NM_001351501.2:c.-24G>A		5 prime UTR
NM_001351502.2:c.-24G>A		5 prime UTR
NM_006731.2:c.373G>A	NP_006722.2:p.Gly125Ser	missense
NR_147213.2:n.588G>A		non-coding transcript variant
NR_147214.2:n.496G>A		non-coding transcript variant
NC_000009.12:g.105604218G>A
NC_000009.11:g.108366499G>A
NG_008754.1:g.51089G>A
LRG_434:g.51089G>A
LRG_434t1:c.373G>A	LRG_434p1:p.Gly125Ser
LRG_434t2:c.373G>A	LRG_434p2:p.Gly125Ser
	O75072:p.Gly125Ser

... more HGVS ... less HGVS

Protein change

G125S, G102S

Other names

p.G125S:GGC>AGC

Canonical SPDI

NC_000009.12:105604217: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.

0.03714 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.01382

Exome Aggregation Consortium (ExAC) 0.01532

The Genome Aggregation Database (gnomAD) 0.03359

Trans-Omics for Precision Medicine (TOPMed) 0.03479

1000 Genomes Project 0.03714

1000 Genomes Project 30x 0.03904

Links

ClinGen: CA252623 UniProtKB: O75072#VAR_033926 OMIM: 607440.0012 dbSNP: rs34006675 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.
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	Likely benign (2)	criteria provided, single submitter	Apr 27, 2017	RCV000003366.15
Walker-Warburg congenital muscular dystrophy	Benign (2)	criteria provided, single submitter	Feb 1, 2024	RCV000460207.20
not specified	Benign (6)	criteria provided, multiple submitters, no conflicts	Oct 31, 2013	RCV000079434.29
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	May 27, 2015	RCV000620119.11
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Nov 17, 2023	RCV001794430.18

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 (Apr 16, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	AllHighlyPenetrant (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000151170.1 First in ClinVar: May 17, 2014 Last updated: May 17, 2014
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: SCV000306354.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Dec 06, 2012)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111313.8 First in ClinVar: Jan 17, 2014 Last updated: Oct 02, 2016	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: 3 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: SCV000557842.7 First in ClinVar: Apr 17, 2017 Last updated: Feb 14, 2024
Benign (Nov 17, 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: SCV000885465.7 First in ClinVar: Feb 18, 2019 Last updated: Feb 20, 2024
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005224816.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Oct 31, 2013)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000168564.10 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)
Likely benign (Apr 27, 2017)	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: SCV001329721.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (1) PubMed: 18177472 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (May 27, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000735198.5 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)
Uncertain significance (Jan 12, 2011)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000023524.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2014	Publications: PubMed (2) PubMed: 21228398‚ 18177472 Comment on evidence: This variant, formerly titled WALKER-WARBURG SYNDROME, FKTN-RELATED, has been reclassified based on the findings of Bell et al. (2011). In a Spanish female infant diagnosed … (more) This variant, formerly titled WALKER-WARBURG SYNDROME, FKTN-RELATED, has been reclassified based on the findings of Bell et al. (2011). In a Spanish female infant diagnosed with Walker-Warburg syndrome (MDDGA4; 253800), who died at day 5 of life, Cotarelo et al. (2008) identified compound heterozygosity for a 373G-A transition in exon 5 of the FKTN gene, resulting in a gly125-to-ser (G125S) substitution, and a 473-bp deletion in exon 10 of the FKTN gene (607440.0013) that includes the polyadenylation signal. The patient was not a carrier of the founder retrotransposal insertion (607440.0001). In a preconception carrier screen for 448 severe recessive childhood diseases involving 437 target genes, Bell et al. (2011) found that the G125S mutation in FKTN is a polymorphism carried by unaffected individuals. (less)
Benign (-)	no assertion criteria provided Method: clinical testing	not specified 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: SCV001973047.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
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) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035935.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Benign (Oct 28, 2019)	no assertion criteria provided Method: clinical testing	Walker-Warburg congenital muscular dystrophy Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002079564.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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: SCV001929401.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
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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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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.

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
Carrier testing for severe childhood recessive diseases by next-generation sequencing.	Bell CJ	Science translational medicine	2011	PMID: 21228398
Two new patients bearing mutations in the fukutin gene confirm the relevance of this gene in Walker-Warburg syndrome.	Cotarelo RP	Clinical genetics	2008	PMID: 18177472
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FKTN	-	-	-	-

Text-mined citations for rs34006675 ...

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_001079802.2(FKTN):c.373G>A (p.Gly125Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs34006675 ...