Submissions for variant NM_053025.4(MYLK):c.2462+5G>A

gnomAD frequency: 0.00008  dbSNP: rs374003770

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598662	SCV000710748	uncertain significance	not provided	2021-06-21	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Intronic +5 splice site variant, both splice predictors and evolutionary conservation support a deleterious effect; however, in the absence of functional evidence, the actual effect of this sequence change is unknown; Not located in the smooth muscle isoform, where the majority of loss-of-function variants associated with autosomal dominant TAAD and autosomal recessive MMIHS have been reported to date (Wang et al., 2010; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 2290495; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533)
Invitae	RCV000707577	SCV000836678	uncertain significance	Aortic aneurysm, familial thoracic 7	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the MYLK gene. It does not directly change the encoded amino acid sequence of the MYLK protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs374003770, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 504425). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Baylor Genetics	RCV000707577	SCV001523647	uncertain significance	Aortic aneurysm, familial thoracic 7	2019-06-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic	RCV000598662	SCV001714703	uncertain significance	not provided	2019-05-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798916	SCV002043662	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2020-12-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001798916	SCV002738213	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-03-01	criteria provided, single submitter	clinical testing	The c.2462+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 14 in the MYLK gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002476346	SCV002791770	uncertain significance	Aortic aneurysm, familial thoracic 7; Megacystis-microcolon-intestinal hypoperistalsis syndrome 1	2022-05-17	criteria provided, single submitter	clinical testing