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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Variant: NM_000257.4(MYH7):c.1925C>T (p.Ser642Leu)

CA011471

14113 (ClinVar)

Gene: MYH7
Condition: hypertrophic cardiomyopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b2041e18-1872-4fea-aad6-a1ddb0b85178

HGVS expressions

NM_000257.4:c.1925C>T
NM_000257.4(MYH7):c.1925C>T (p.Ser642Leu)
ENST00000355349.4:c.1925C>T
ENST00000355349.3:c.1925C>T
NM_000257.3:c.1925C>T
NC_000014.9:g.23427271G>A
CM000676.2:g.23427271G>A
NC_000014.8:g.23896480G>A
CM000676.1:g.23896480G>A
NC_000014.7:g.22966320G>A
NG_007884.1:g.13391C>T

Uncertain Significance

Met criteria codes 2
PM2 PS4_Supporting
Not Met criteria codes 18
PM6 PM1 PM4 PM5 PVS1 BS3 BS4 BS1 BP2 BP5 BP7 BP4 PS3 BA1 PS2 PS1 PP1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cardiomyopathy VCEP
TThe c.1925C>T (p.Ser642Leu) variant in MYH7 has been identified in 4 individuals with DCM (PS4_Supporting; Daehmlow 2002 PMID:12379228; OMGL pers. comm., Invitae pers. comm., Ambry pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PM2; PS4_Supporting
Met criteria codes
PM2
Absent from gnomAD. Neighboring variants have coverage in >250,000 samples.
PS4_Supporting
Identified in 4 probands with DCM: 1 in the literature, 3 from VCC labs (1 Invitae, 1 Ambry - also has a VUS in ACTN2; 1 OMGL - also has VUSes DSC2 c.907G>C, FLNC c.4159A>G, MYBPC3 c.2687T>G).
Not Met criteria codes
PM6
No reports of de novo inheritance
PM1
Located in the myosin head domain. however this association is with HCM and cannot be used to support pathogenicity for other phenotypes, therefore PM1 is not applied
PM4
Does not change protein length
PM5
No other variants reported at this position
PVS1
No of null variant.
BS3
No reported functional assays.
BS4
No reported lack of segregation.
BS1
Absent from gnomAD. Neighboring variants have coverage in >250,000 samples.
BP2
Not reported with a pathogenic variant.
BP5
Not found in a case with an alternate molecular basis.
BP7
Not a synonymous variant.
BP4
Predicted damaging by SIFT, PolyPhen2, and REVEL.
PS3
No reported functional assays.
BA1
Absent from gnomAD. Neighboring variants have coverage in >250,000 samples.
PS2
No reports of de novo inheritance
PS1
No other variants reported at this position
PP1
No reported segregation.
PP3
Predicted damaging by SIFT, PolyPhen2, and REVEL. (Sfit in alamut tolerated.... Trends in REVEL not all pointing to effect -HZ)
Approved on: 2021-06-16
Published on: 2021-06-16
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