rs786205597

Positions:

• chr9-105601293-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_001079802.2(FKTN):​c.314G>T​(p.Cys105Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C105Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FKTN NM_001079802.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 8.09

Genes affected

FKTN (HGNC:3622): (fukutin) The protein encoded by this gene is a putative transmembrane protein that is localized to the cis-Golgi compartment, where it may be involved in the glycosylation of alpha-dystroglycan in skeletal muscle. The encoded protein is thought to be a glycosyltransferase and could play a role in brain development. Defects in this gene are a cause of Fukuyama-type congenital muscular dystrophy (FCMD), Walker-Warburg syndrome (WWS), limb-girdle muscular dystrophy type 2M (LGMD2M), and dilated cardiomyopathy type 1X (CMD1X). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-105601293-G-A is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 9-105601293-G-T is Pathogenic according to our data. Variant chr9-105601293-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191237.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}. Variant chr9-105601293-G-T is described in Lovd as [Likely_pathogenic]. Variant chr9-105601293-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FKTN	NM_001079802.2	c.314G>T	p.Cys105Phe	missense_variant	5/11	ENST00000357998.10	NP_001073270.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FKTN	ENST00000357998.10	c.314G>T	p.Cys105Phe	missense_variant	5/11	5	NM_001079802.2	ENSP00000350687	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, flagged submission

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

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Myopathy caused by variation in FKTN Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Cardiomyopathy, dilated, 1X (MIM#611615), congenital muscular dystrophy type A, 4 (MIM#253800), type B, 4 (MIM#613152) and limb-girdle muscular dystophy, type C, 4 (MIM#611588) (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. Although the p.C105Y missense variant has been classified in LOVD as likely pathogenic, there was no evidence provided to support pathogenicity and therefore could not be considered. (I) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. The p.Cys105Phe variant has been reported in one Limb-Girdle Muscular Dystrophy family, where muscle biopsy of the affected individual demonstrated dystrophic or myopathic changes (PMID: 27671536). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;D;.;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-4.0	.;D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.96
MutPred		0.88		Gain of ubiquitination at K102 (P = 0.0686);Gain of ubiquitination at K102 (P = 0.0686);Gain of ubiquitination at K102 (P = 0.0686);Gain of ubiquitination at K102 (P = 0.0686);
MVP		0.90
MPC		0.55
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.79
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786205597; hg19: chr9-108363574;