Submissions for variant NM_001079802.2(FKTN):c.1337A>T (p.Asn446Ile) (rs374912618)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498728	SCV000589960	uncertain significance	not provided	2018-08-13	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the FKTN gene. The N446I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N446I variant is observed in 40/16,510 (0.2%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The N446I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with alpha-dystroglycanopathies (Stenson et al., 2014). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV001082102	SCV000755355	likely benign	Walker-Warburg congenital muscular dystrophy	2019-12-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001167905	SCV001330451	uncertain significance	Dilated cardiomyopathy 1X	2018-01-13	criteria provided, single submitter	clinical testing	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.
Illumina Clinical Services Laboratory,Illumina	RCV001167906	SCV001330452	uncertain significance	Fukuyama congenital muscular dystrophy	2018-01-13	criteria provided, single submitter	clinical testing	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.