ClinVar Miner

Submissions for variant NM_053025.4(MYLK):c.1007C>T (p.Pro336Leu) (rs35912339)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000173911 SCV000225087 benign not specified 2015-05-21 criteria provided, single submitter clinical testing
Invitae RCV001082109 SCV000291185 benign Aortic aneurysm, familial thoracic 7 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000241731 SCV000319547 likely benign Cardiovascular phenotype 2019-03-22 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
GeneDx RCV000173911 SCV000530487 likely benign not specified 2017-11-02 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000680576 SCV000807991 likely benign Connective tissue disease 2018-06-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757536 SCV000885796 likely benign not provided 2018-05-04 criteria provided, single submitter clinical testing The c.1007C>T; p.Pro336Leu variant (rs35912339, ClinVar variant ID 193752), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.4% (identified on 120 out of 30,782 chromosomes). The proline at position 336 is weakly conserved, considering 12 species, and computational analyses of the effects of the p.Pro336Leu variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the p.Pro336Leu variant is likely to be benign.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769342 SCV000900725 likely benign Familial thoracic aortic aneurysm and aortic dissection 2016-07-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001082109 SCV001311719 likely benign Aortic aneurysm, familial thoracic 7 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Integrated Genetics/Laboratory Corporation of America RCV000173911 SCV001338137 benign not specified 2020-02-03 criteria provided, single submitter clinical testing Variant summary: MYLK c.1007C>T (p.Pro336Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0016 in 248810 control chromosomes, including 1 homozygote (gnomAD). The variant was predominantly observed within the South Asian subpopulation (at a frequency of 0.0039), and the European (non-Finnish) subpopulation (at a frequency of 0.0021) in the gnomAD database. These frequencies are approximately 150-fold and 85-fold higher (respectively) than the estimated maximal expected allele frequency for a pathogenic variant in MYLK causing Aortopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1007C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (2x) / likely benign (5x). Based on the evidence outlined above, the variant was classified as benign.

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