Submissions for variant NM_006790.3(MYOT):c.1401T>A (p.Asn467Lys)

dbSNP: rs145427063

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000529217	SCV000453022	uncertain significance	Myofibrillar myopathy 3	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 Laboratory Services, Illumina	RCV000367931	SCV000453023	uncertain significance	Limb-Girdle Muscular Dystrophy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000391315	SCV000453024	uncertain significance	Myofibrillar Myopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487879	SCV000575441	uncertain significance	not provided	2016-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000487879	SCV000589346	uncertain significance	not provided	2017-06-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYOT gene. The N467K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The N467K variant is observed in 1/6,614 (0.015%) alleles from individuals of Finnish background in large population cohorts (Lek et al., 2016). The N467K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000529217	SCV000638808	uncertain significance	Myofibrillar myopathy 3	2023-09-03	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 467 of the MYOT protein (p.Asn467Lys). This variant is present in population databases (rs145427063, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MYOT-related conditions. ClinVar contains an entry for this variant (Variation ID: 351029). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.
Eurofins Ntd Llc (ga)	RCV000487879	SCV000707808	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000529217	SCV000897204	uncertain significance	Myofibrillar myopathy 3	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523508	SCV003691549	uncertain significance	Inborn genetic diseases	2022-10-12	criteria provided, single submitter	clinical testing	The c.1401T>A (p.N467K) alteration is located in exon 10 (coding exon 9) of the MYOT gene. This alteration results from a T to A substitution at nucleotide position 1401, causing the asparagine (N) at amino acid position 467 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000529217	SCV003810959	uncertain significance	Myofibrillar myopathy 3	2023-01-13	criteria provided, single submitter	clinical testing