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]
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  • See Evidence submitted by expert panel for details.

Variant: NM_000257.4(MYH7):c.4499G>A (p.Arg1500Gln)

CA015036

180439 (ClinVar)

Gene: MYH7
Condition: cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 7bd8b7e1-5ac6-43a5-81b2-500bcd125706

HGVS expressions

NM_000257.4:c.4499G>A
NM_000257.4(MYH7):c.4499G>A (p.Arg1500Gln)
NC_000014.9:g.23417173C>T
CM000676.2:g.23417173C>T
NC_000014.8:g.23886382C>T
CM000676.1:g.23886382C>T
NC_000014.7:g.22956222C>T
NG_007884.1:g.23489G>A
ENST00000355349.4:c.4499G>A
ENST00000355349.3:c.4499G>A
NM_000257.3:c.4499G>A
NR_126491.1:n.652-39C>T

Uncertain Significance

Met criteria codes 2
PM2 PP3
Not Met criteria codes 22
PVS1 PM4 PM6 PM1 PM5 PM3 BA1 BS4 BS3 BS1 BS2 BP7 BP5 BP2 BP4 BP3 PS2 PS4 PS1 PS3 PP1 PP4

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.4499G>A (p.Arg1500Gln) variant has been reported in at least 1 individual with features of ARVC and DCM (Murray 2018 PMID:29709087; Ambry pers. comm), as well as individuals with less specific cardiac features (GeneDx pers. comm.); however these data are insufficient to apply PS4. This variant was identified in 0.0007% (FAF 95% CI; 3/113770) of European chromosomes by gnomAD v2.1.1 (PM2; https://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to insufficient 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): PM2, PP3.
Met criteria codes
PM2
Variant seen in 0.0007% (FAF 95% CI; 3/113770) of European (non-Finnish) chromosomes in gnomAD v2.1.1
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Not Met criteria codes
PVS1
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
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
Variant is outside the region of enrichment.
PM5
Variants that disrupt the p.Arg1500 amino acid residue in MYH7 have been observed in individuals with DCM and myopathy (PMID: 15556047, 18660445, 19412328, 24119082). See ClinVar entries. Neither has sufficient evidence to be pathogenic on its own, therefore these are will not be fully assessed and the criterion is not met.
PM3
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
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
BS2
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
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
Position is well conserved and all tools, including REVEL, supportive of an impact.
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
Variant is present 3 times in Clinvar, but phenotypes are not consistent or not reported. Internal data log suggests variant has been seen by two labs, but once again phenotypes not consistent. One paper (PMID: 29709087) reports this variant in a proband with ARVC (no segregations). This variant has been reported in at least 1 individual with features of ARVC and DCM (Murray 2018 PMID:29709087; Ambry pers. comm), as well as individuals with less specific cardiac features (GeneDx pers. comm.); however these data are insufficient to apply PS4.
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2021-01-22
Published on: 2021-10-01
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