×

Please note this is a beta version of the ClinGen Evidence Repository. This resource is intended to provide access to variant level evidence used and applied by ClinGen Variant Curation Expert Panels in the classification of variants. In this beta version, the evidence is limited to curation notes and referenced literature (PMIDs).

For general information about ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding a variant classification or evidence curation (e.g. population database queried, segregation counts or other evidence used) or to submit general comments about the evidence repo, please email us.

The resource is undergoing updates and tesing. Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know so we can rectify these accordingly. Your help in this regard is greatly appreciated.

Criteria Specification: CSpec Registry PDF

Variant: NM_000257.4(MYH7):c.728G>A (p.Arg243His)

CA016701

14126 (ClinVar)

Gene: MYH7
Condition: cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance

HGVS expressions

NM_000257.4:c.728G>A
NM_000257.4(MYH7):c.728G>A (p.Arg243His)
ENST00000355349.4:c.728G>A
ENST00000355349.3:c.728G>A
NM_000257.3:c.728G>A
NC_000014.9:g.23431589C>T
CM000676.2:g.23431589C>T
NC_000014.8:g.23900798C>T
CM000676.1:g.23900798C>T
NC_000014.7:g.22970638C>T
NG_007884.1:g.9073G>A

Uncertain Significance

Met criteria codes 3
PP3 PM2 PS4_Supporting
Unmet criteria codes 14
BS4 BS3 BS1 BP5 BP2 BP4 PS3 PS2 PS1 PP1 PM6 PM1 PM5 BA1

Evidence Links 0

Evidence submitted by expert panel
Cardiomyopathy VCEP
The c.728G>A (p.Arg243His) variant in MYH7 has been identified in 3 individuals with HCM (Arad 2005 PMID:16267253; van Velzen 2016 PMID:27476098; GeneDx pers. comm.), 2 individuals with DCM (one of whom carried a VUS in another DCM gene; Walsh 2017 PMID:27532257; GeneDx pers. comm.), 1 individual with LVNC, dilation, and congestive heart failure prior to transplant at 26 yo - Klaassen 2008 PMID:18506004) and 6 individuals with LVNC or non-compaction cardiomyopathy (van Waning 2018 29447731; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.). This variant segregated in 7 individuals with LVNC, 1 with LV dysfunction, and 1 with DCM from 5 families (Klaassen et al 2008, PMID 18506004; GeneDx, pers. comm.; Invitae, pers. comm.; OMGL, pers. comm.). While this variant has been reported in multiple phenotypes, there is conflicting evidence on whether isolated LVNC is a Mendelian disease and therefore those cases without additional cardiomyopathy features are not currently being counted. Therefore, the PS4_Supporting criterion is being applied for the DCM phenotypes. Additionally, current evidence is insufficient to establish segregation with DCM or HCM and therefore the PP1 criterion has not been applied. This variant was identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes that are predominant for this variant; therefore PM1 is not applicable. Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to variable and conflicting evidence, this variant is classified as uncertain significance for inherited cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting, PM2, PP3.
Met criteria codes
PP3
Deleterious effect predicted by Polyphen, SIFT, Mutation Taster, PROVEAN; REVEL score consistent
PM2
This variant was identified in 0.003% (1/34592) of Latino chromosomes in gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). This variant was identified in 0.001% (2/251492) total alleles in gnomAD v2.1.1 (https://gnomad.broadinstitute.org).
PS4_Supporting
This variant has been identified in 3 individuals with HCM (Arad 2005 PMID:16267253; van Velzen 2016 PMID:27476098; GeneDx pers. comm.), 2 individuals with DCM (Walsh 2017 PMID:27532257; GeneDx pers. comm.), 1 individual with LVNC, dilation, and congestive heart failure prior to transplant at 26 yo - Klaassen 2008 PMID:18506004) and 6 individuals with LVNC or non-compaction cardiomyopathy (van Waning 2018 29447731; Walsh 2017 PMID:27532257; GeneDx pers. comm.; Invitae pers. comm.) Probands counted = 3 HCM, 2 DCM, 1 LVNC + DCM/CHF, 6 LVNC Literature: 2 HCM (PMIDs 27476098, 16267253) 2 DCM (PMID 27532257) 1 LVNC + CHF (PMID 18506004) 2 LVNC (PMID 29447731, 27532257), including 1 requiring transplant at 26 yo (PMID 18506004) Lab Internal Data: GeneDx: 1 HCM, 2 LVNC; 2 segregations in 2 families (1 with LV dysfunction and 1 with abnormal echo); 1 DCM (with VCL VUS p.Ile431Ser) Invitae: 2 LVNC with 3 family members with LVNC from 1 family OMGL: Segregation in 1 affected relative (DCM) Probands not counted: OMGL: 1 DCM; 1 LVNC and Ebstein's anomaly and segregated with LVNC in 2 relatives since counted as PMID 27532257
Unmet criteria codes
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
PMIDs 28606303 and 27247418 computation modeling studies, PS3 not applicable
PS2
No de novo data
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
This variant segregated in 7 individuals with LVNC, 1 with LV dysfunction, and 1 with DCM from 5 families (Klaassen et al 2008, PMID 18506004; GeneDx, pers. comm.; Invitae, pers. comm.; OMGL, pers. comm.). Segregations counted = 9 (8 if only counting LVNC) 2 literature 2 LVNC (PMID 18506004) 7 internal lab data 1 DCM OMGL 1 LV dysfunction (GeneDx) 5 LVNC (3 Invitae + 2 OMGL) Not counted: PMID 18506004 child not counted bc explicit confirmation of genotype not found in article 1 LVNC GeneDx seg/family not counted for unspecified 'abnormal echo'
PM6
No de novo data
PM1
Missense variant within head domain (codons 181-937; Walsh et al., PMID 27532257); but predominant phenotype is not HCM, so not counting.
PM5
R243C (c.727C>T) not expected to reach Pathogenic based on GeneDx internal review (no strong criteria likely to be applicable); new VCI curation not created; publications entered below MAK - Agree, also for HCM where this variant appears to be more LVNC.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-06-16
Published on: 2021-06-16
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.