Submissions for variant NM_000257.4(MYH7):c.5470_5471delinsGG (p.Asn1824Gly)

dbSNP: rs1595071680

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809757	SCV000949931	uncertain significance	Hypertrophic cardiomyopathy	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine with glycine at codon 1824 of the MYH7 protein (p.Asn1824Gly). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and glycine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of MYH7-related conditions (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 653905). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Color Diagnostics, LLC DBA Color Health	RCV001182272	SCV001347667	uncertain significance	Cardiomyopathy	2022-09-12	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion and insertion, resulting in a missense and replacing asparagine with glycine at codon 1824 of the MYH7 protein. To our knowledge, functional studies have not been reported for this variant. Splice site prediction tools suggest that this variant may impact RNA splicing. This variant has been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 30847666). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001824379	SCV002073999	uncertain significance	not provided	2021-08-13	criteria provided, single submitter	clinical testing	Reported in an individual with arrhythmogenic right ventricular cardiomyopathy (ARVC), however further clinical information was not provided (van Lint FHM et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 26582918, 30847666)
Ambry Genetics	RCV002345829	SCV002654307	uncertain significance	Cardiovascular phenotype	2024-03-01	criteria provided, single submitter	clinical testing	The c.5470_5471delAAinsGG variant, located in coding exon 35 of the MYH7 gene, results from an in-frame deletion of AA and insertion of GG at nucleotide positions 5470 to 5471. This results in the substitution of the asparagine residue for a glycine residue at codon 1824, an amino acid with similar properties. This variant was detected in a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected in some cases (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012;7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002487750	SCV002786799	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001824379	SCV003815396	uncertain significance	not provided	2019-12-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003489901	SCV004241669	uncertain significance	not specified	2023-12-04	criteria provided, single submitter	clinical testing	Variant summary: MYH7 c.5470_5471delinsGG (p.Asn1824Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Three of three in-silico tools predict a damaging effect of the variant on protein function. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5470_5471delinsGG has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence for causality (vanLint_2019). This report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30847666). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.