Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • See Evidence submitted by expert panel for details.

Variant: NM_000257.3(MYH7):c.5329G>A (p.Ala1777Thr)

CA015952

177697 (ClinVar)

Gene: MYH7
Condition: cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a16a1f02-844a-4b61-bd74-71c8230a85de
Approved on: 2021-11-30
Published on: 2021-12-09

HGVS expressions

NM_000257.3:c.5329G>A
NM_000257.3(MYH7):c.5329G>A (p.Ala1777Thr)
NC_000014.9:g.23415225C>T
CM000676.2:g.23415225C>T
NC_000014.8:g.23884434C>T
CM000676.1:g.23884434C>T
NC_000014.7:g.22954274C>T
NG_007884.1:g.25437G>A
ENST00000355349.4:c.5329G>A
ENST00000355349.3:c.5329G>A
NM_000257.4:c.5329G>A
NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr)
More

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "[unknown]"
Not Met criteria codes 25
PVS1 BA1 PS3 PS2 PS1 PS4 PP1 PP3 PP2 PM4 PM3 PM6 PM1 PM5 PM2 BS2 BS3 BS4 BS1 BP3 BP1 BP7 BP5 BP2 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
The NM_000257.4(MYH7):c.5329G>A (p.Ala1777Thr) variant has been identified in at least 14 individuals with HCM, 2 of whom had an additional variant in another gene that may contribute to their disease, 1 individual with RCM with another pathogenic MYH7 variant, and 5 individuals with DCM including 2 that also had disease-causing variants (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID: 27532257; Ho 2018 PMID:30297972; Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm). This variant has also been identified in 1 individual with LVNC requiring transplant who also had 2 pathogenic MYBPC3 variants, 1 individual with Brugada syndrome, and 2 individuals with myopathy - 1 with myofibrillar myopathy and 1 with distal and axial myopathy (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). This variant has been observed to segregate with DCM in 1 relative of a proband with DCM as well as not segregate with HCM in an affected sibling of a proband with HCM (OMGL per. comm.). Because of the variability in phenotypes observed in individuals with this variant and because PS4 is only applicable when the variant is absent or rare in large population studies, the PS4 criterion was not applied (Kelly 2018 PMID:29300372). Additionally, the segregation data is currently insufficient to establish segregation or non-segregation with disease and therefore neither PP1 nor BS4 were applied. This variant has been identified in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1 (http://gnomad.broadinstitute.org) and is above the threshold of 0.004%, therefore PM2 cannot be applied. Computational prediction tools and conservation do not provide evidence for or against an impact to the protein. In summary, due to conflicting evidence, this variant is classified as uncertain significance for cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): None.
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
This variant is reported in a PhD thesis which performed a number of functional studies, however the results have not been subsequently reported in the published literature. Author William Wallefeld, University of Western Australia, primary supervisor Dr Nigel Liang. Results not sufficient to apply this criteria.
PS2
Updated 2021: data not available to assess this criteria
PS1
No other variants affecting the same AA reported.
PS4
Variant has been identified in: 6 individuals with HCM in the literature (Richard 2003 PMID:12707239; Bos 2014 PMID:24793961; Homburger 2016 PMID:27247418; Walsh 2017 PMID: 27532257; Ho 2018 PMID:30297972). 8 individuals with HCM from internal data (2 with other disease-causing variants; splice and nonsense in MYBPC3), 1 RCM with another MYH7 missense considered path by this VCEP), & 5 DCM (2 have TTN LP variants)(Ambry pers. comm.; GeneDx pers. comm.; LMM pers. comm.; OMGL pers. comm) it was also seen in 1 LVNC requiring transplant with 2 pathogenic MYBPC3 variants, 1 Brugada syndrome, 1 myofibrillar myopathy, 1 patient with distal & axial myopathy, (Hertz 2014 PMID:25467552; Evilä 2016 PMID:26627873; Chanson 2016 PMID:26969127; Liu 2020 PMID:31918855). Literature search complete: ClinVar, Google, HGMD INTERNAL DATA: Ambry 1 HCM, 1 GI symptoms, heart disease, renal issues; HCM proband with MYBPC3 c.3330+1G>T VLP GeneDx 3 HCM, 3 DCM; 1 of the HCM probands has no clinical information provided to support the HCM diagnosis. All 3 of the DCM probands have other varaints reported (one has a TTN LPath; another has VUS on RYR2, RBM20 and LDB3 and the third one has a family history of HCM and DCM and VUS on MYH7, DSP and TPM1) Invitae 3 HCM, 1 DCM, 1 LQTS; 1 DCM proband also has Likely Pathogenic variant in TTN (NM_001267550.2:c.52847G>A (p.Trp17616*)), 1 HCM proband has Path MYBPC3 p.Gln404* variant LMM 1 RCM that had another MYH7 variant (p.Arg453Cys - pathogenic by this EP) OMGL 1 HCM (+2 HCM in Walsh paper) and 1 non-segregation with HCM (not detected in affected sister of one HCM proband), 1 DCM and 1 segregation with DCM
PP1
1 non-segregation from OMGL lab (internal data), variant did not segregate to affected sister of proband
PP3
In silico tools are mixed on predicted impact and REVEL is below threshold.
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
Updated 2021: data not available to assess this criteria
PM1
Variant is located outside of the head domain
PM5
No other variants affecting the same AA reported.
PM2
Variant seen in 0.008% (FAF 95% CI; 17/129,190) of European chromosomes in gnomAD v.2.1.1
BS2
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
BS4
1 non-segregation from OMGL lab (internal data), variant did not segregate to affected sister of proband
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
Updated 2021: no reports found to support this criteria
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
Curation History
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.