Submissions for variant NM_000257.4(MYH7):c.3726+6C>T (rs377745688)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000035863	SCV000059514	uncertain significance	not specified	2014-09-19	criteria provided, single submitter	clinical testing	The 3726+6C>T variant in MYH7 has been identified by our laboratory in 2 Caucasi an adults with HCM, one of whom carries a pathogenic variant in the MYBPC3 gene. This variant has also been identified in 4/8600 of European American chromosome s by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSN P rs377745688). This variant is located in the 5' splice region. Computational t ools do not suggest an impact to splicing. However, this information is not pred ictive enough to rule out pathogenicity. In summary, the clinical significance o f the 3726+6C>T variant is uncertain.
GeneDx	RCV000035863	SCV000208429	uncertain significance	not specified	2017-06-20	criteria provided, single submitter	clinical testing	The variant is found in HCM panel(s). A variant of uncertain significance has been identified in the MYH7 gene. The c.3726+6 C>T variant has been reported previously as a variant of uncertain significance in an individual with apical HCM; however, additional clinical information was not provided and information regarding parental testing was not available (Gruner et al., 2011). The c.3726+6 C>T variant is observed in 12/66732 (0.2%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In-silico splice prediction models are inconsistent in their predictions as to whether or not c.3726+6 C>T may create a cryptic splice donor site which may supplant the natural donor site and lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000549671	SCV000623703	likely benign	Hypertrophic cardiomyopathy	2019-12-31	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001110078	SCV001267468	uncertain significance	Myosin storage myopathy	2018-06-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001110079	SCV001267469	uncertain significance	Familial hypertrophic cardiomyopathy 1	2018-06-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001114108	SCV001271943	benign	Myopathy, distal, 1	2018-06-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Color	RCV001182249	SCV001347637	likely benign	Cardiomyopathy	2019-01-11	criteria provided, single submitter	clinical testing