Submissions for variant NM_000257.4(MYH7):c.968T>C (p.Ile323Thr)

gnomAD frequency: 0.00006  dbSNP: rs397516275

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000036013	SCV000059665	uncertain significance	not specified	2013-02-08	criteria provided, single submitter	clinical testing	The Ile323Thr variant in MYH7 has not been reported in the literature nor previo usly identified by our laboratory. This variant has also not been identified in large European American and African American populations by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS), though it may be common in ot her populations. Computational analyses (biochemical amino acid properties, cons ervation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or a gainst an impact to the protein but another variant at the same position (Ile323 Asn) has been classified as likely pathogenic for HCM (LMM unpublished data). In summary, additional information is needed to fully assess the clinical signific ance of the Ile323Thr variant.
GeneDx	RCV000588549	SCV000208710	uncertain significance	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Reported in association with HCM (Walsh et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34542152, 31977013, 27532257, 29300372)
Ambry Genetics	RCV000251862	SCV000317477	uncertain significance	Cardiovascular phenotype	2022-12-23	criteria provided, single submitter	clinical testing	The p.I323T variant (also known as c.968T>C), located in coding exon 9 of the MYH7 gene, results from a T to C substitution at nucleotide position 968. The isoleucine at codon 323 is replaced by threonine, an amino acid with similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Walsh R et al. Genet. Med. 2017;19:192-203). This variant has also been detected in a cohort not selected for the presence of cardiovascular disease; however, details were limited (Park J et al. Hum Mol Genet. 2022 Mar;31(5):827-837). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000528203	SCV000623764	uncertain significance	Hypertrophic cardiomyopathy	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 323 of the MYH7 protein (p.Ile323Thr). This variant is present in population databases (rs397516275, gnomAD 0.04%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy or cardiac conduction disease (PMID: 27532257, 31977013). ClinVar contains an entry for this variant (Variation ID: 43115). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588549	SCV000696360	uncertain significance	not provided	2016-02-15	criteria provided, single submitter	clinical testing	Variant summary: The c.968T>C variant affects a conserved nucleotide, resulting in amino acid change from Ile to Thr. 5/5 in-silico tools predict damaging outcome for this variant. 5/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions are not confirmed by experimental studies. This variant is found in 9/119224 control chromosomes at a frequency of 0.0000755, which does not exceed the maximal expected frequency of a pathogenic allele (0.0010005) in this gene. Two clinical laboratories classified this variant as VUS and likely pathogenic, respectively, without providing evidence for independent review. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories, nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170743	SCV001333346	uncertain significance	Cardiomyopathy	2022-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170743	SCV001357327	uncertain significance	Cardiomyopathy	2023-12-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 323 of the MYH7 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257) and in one individual affected with cardiac conduction system disease (PMID: 31977013). This variant has been identified in 16/251322 chromosomes 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.
CeGaT Center for Human Genetics Tuebingen	RCV000588549	SCV002585461	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	MYH7: PM2, PP2
Revvity Omics, Revvity	RCV000588549	SCV003817734	uncertain significance	not provided	2022-06-22	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000588549	SCV001924019	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588549	SCV001958237	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000588549	SCV001966235	uncertain significance	not provided		no assertion criteria provided	clinical testing