NM_001079802.2(FKTN):c.1167dup (p.Phe390fs) AND Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 6, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000003356.14

Allele description [Variation Report for NM_001079802.2(FKTN):c.1167dup (p.Phe390fs)]

NM_001079802.2(FKTN):c.1167dup (p.Phe390fs)

Gene:

FKTN:fukutin [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

9q31.2

Genomic location:

Preferred name:

NM_001079802.2(FKTN):c.1167dup (p.Phe390fs)

HGVS:

NC_000009.11:g.108382330_108382331insA
NC_000009.12:g.105620056dup
NG_008754.1:g.66927dup
NM_001079802.2:c.1167dupMANE SELECT
NM_001198963.2:c.1167dup
NM_001351496.2:c.1167dup
NM_001351497.2:c.1098dup
NM_001351498.2:c.1167dup
NM_001351499.2:c.771dup
NM_001351500.2:c.771dup
NM_001351501.2:c.771dup
NM_001351502.2:c.771dup
NM_006731.2:c.1167dup
NP_001073270.1:p.Phe390fs
NP_001185892.1:p.Phe390fs
NP_001338425.1:p.Phe390fs
NP_001338426.1:p.Phe367fs
NP_001338427.1:p.Phe390fs
NP_001338428.1:p.Phe258fs
NP_001338429.1:p.Phe258fs
NP_001338430.1:p.Phe258fs
NP_001338431.1:p.Phe258fs
NP_006722.2:p.Phe390fs
LRG_434t2:c.1167dup
LRG_434:g.66927dup
LRG_434p2:p.Phe390fs
NC_000009.11:g.108382330_108382331insA
NC_000009.11:g.108382337dup
NC_000009.11:g.108382337dupA
NM_001079802.1:c.1167dupA
NM_001079802.2:c.1167dup
NM_006731.2:c.1167dupA
NR_147213.2:n.1118dup
NR_147214.2:n.1290dup
c.1167dupA (p.Phe390Ilefs*14)
c.1167insA

Note:

NCBI staff reviewed the sequence information reported in PubMed 10545611 Fig. 3 to determine the location of this allele on the current reference sequence.

Protein change:

F258fs

Links:

OMIM: 607440.0005; dbSNP: rs398123555

NCBI 1000 Genomes Browser:

rs398123555

Molecular consequence:

NM_001079802.2:c.1167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001198963.2:c.1167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351496.2:c.1167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351497.2:c.1098dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351498.2:c.1167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351499.2:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351500.2:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351501.2:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001351502.2:c.771dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_006731.2:c.1167dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_147213.2:n.1118dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_147214.2:n.1290dup - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 (MDDGA4)
Synonyms:: Fukuyama type muscular dystrophy; Muscular dystrophy, congenital progressive, with mental retardation; Muscular dystrophy, congenital, with central nervous system involvement; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009678; MedGen: C0410174; Orphanet: 588; Orphanet: 899; OMIM: 253800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000023514	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2008)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 18177472, 17044012, 10545611
SCV000698716	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 18, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18177472, 17878207 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001163214	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193928	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Nov 15, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 19266496, 18752264, 17878207, 10545611, 18177472, 24144914 Citation Link,
SCV002767381	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19266496, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Fukutin gene mutations in steroid-responsive limb girdle muscular dystrophy.

Godfrey C, Escolar D, Brockington M, Clement EM, Mein R, Jimenez-Mallebrera C, Torelli S, Feng L, Brown SC, Sewry CA, Rutherford M, Shapira Y, Abbs S, Muntoni F.

Ann Neurol. 2006 Nov;60(5):603-610. doi: 10.1002/ana.21006.

PubMed [citation]

PMID:: 17044012

Ethnically diverse causes of Walker-Warburg syndrome (WWS): FCMD mutations are a more common cause of WWS outside of the Middle East.

Manzini MC, Gleason D, Chang BS, Hill RS, Barry BJ, Partlow JN, Poduri A, Currier S, Galvin-Parton P, Shapiro LR, Schmidt K, Davis JG, Basel-Vanagaite L, Seidahmed MZ, Salih MA, Dobyns WB, Walsh CA.

Hum Mutat. 2008 Nov;29(11):E231-41. doi: 10.1002/humu.20844.

PubMed [citation]

PMID:: 18752264
PMCID:: PMC2577713

See all PubMed Citations (8)

Details of each submission

From OMIM, SCV000023514.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

In a girl with severe FCMD (MDDGA4; 253800) including microphthalmia, Kondo-Iida et al. (1999) identified a 1-bp insertion (1279insA) in exon 9 of the FKTN gene, causing a frameshift and a premature stop at codon 403. The patient carried the founder insertion (607440.0001) from her mother; however, the 1-bp insertion could not be detected in the father by either SSCP or by direct sequencing, leading Kondo-Iida et al. (1999) to conclude that this was the first example of a de novo mutation.

In a cell line from an Ashkenazi Jewish male diagnosed with Walker-Warburg syndrome (MDDGA4), Cotarelo et al. (2008) identified homozygosity for a 1-bp insertion within a stretch of 6 adenine residues in exon 9 (1160_1168insA). Cell lines from the unrelated, unaffected parents revealed that they were heterozygous carriers of the insertion.

In 2 sibs and an unrelated child with FKTN-related limb-girdle muscular dystrophy (MDDGC4; 611588), Godfrey et al. (2006) identified compound heterozygosity for mutations in the FKTN gene. All 3 children had a 1-bp insertion in exon 9 (1167insA), which the authors stated was the same mutation as that identified by Kondo-Iida et al. (1999). The insertion was predicted to result in a frameshift at phe390 and premature termination, followed by nonsense-mediated decay of the mRNA transcript. The second mutant allele identified was a 1-bp deletion (607440.0008) in 1 child and a missense mutation (R307Q; 607440.0009) in 2 sibs. The patients showed early-onset proximal muscular dystrophy, normal intelligence and brain structure, and favorable response to steroid treatment.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698716.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163214.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193928.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

NM_001079802.1(FKTN):c.1167dupA(F390Ifs*14) is classified as pathogenic in the context of FKTN-related disorders. Sources cited for classification include the following: PMID 19266496, 18752264, 17878207, 10545611, 18177472 and 24144914. Classification of NM_001079802.1(FKTN):c.1167dupA(F390Ifs*14) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767381.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type 4A (MIM#253800). (I) 0106 - This gene is associated with autosomal recessive disease. Recessive pathogenic variants in this gene can cause three types of muscular dystrophy-dystroglycanopathy: a severe congenital form with brain and eye anomalies (type A4; MIM# 253800), formerly designated Fukuyama congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), or muscle-eye-brain disease (MEB), a less severe congenital form without impaired intellectual development (type B4; MIM# 613152), and a milder limb-girdle form (type C4; MIM# 611588). (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (97 heterozygotes, 0 homozygotes) and is enriched in the Ashkenazi Jewish population. (SP) 0604 - Variant is not predicted to truncate an established domain, motif, hotspot or informative constraint region. (I) 0702 - Other truncating variants comparable to the one identified in this case have strong previous evidence for pathogenicity. At least three downstream truncating variants have previously been classified as pathogenic (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in many individuals with muscular dystrophy-dystroglycanopathies and is considered to be a founder variant in the Ashkenazi Jewish population. When homozygous, the variant results in the severe congenital type 4A form of disease with brain and eye anomalies (MIM#253800), however the type can vary when in compound heterozygosity with a different variant (ClinVar, LOVD, PMID: 19266496). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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