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NM_000257.4(MYH7):c.2722C>G (p.Leu908Val) AND not provided

Germline classification:
Pathogenic (3 submissions)
Last evaluated:
Feb 17, 2022
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000078452.23

Allele description [Variation Report for NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)]

NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)

Gene:
MYH7:myosin heavy chain 7 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
14q11.2
Genomic location:
Preferred name:
NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)
Other names:
p.L908V:CTG>GTG; NM_000257.3(MYH7):c.2722C>G
HGVS:
  • NC_000014.9:g.23424107G>C
  • NG_007884.1:g.16555C>G
  • NM_000257.4:c.2722C>GMANE SELECT
  • NP_000248.2:p.Leu908Val
  • NP_000248.2:p.Leu908Val
  • LRG_384t1:c.2722C>G
  • LRG_384:g.16555C>G
  • LRG_384p1:p.Leu908Val
  • NC_000014.8:g.23893316G>C
  • NM_000257.2:c.2722C>G
  • NM_000257.3:c.2722C>G
  • P12883:p.Leu908Val
  • c.2722C>G
Protein change:
L908V; LEU908VAL
Links:
UniProtKB: P12883#VAR_004593; OMIM: 160760.0010; dbSNP: rs121913631
NCBI 1000 Genomes Browser:
rs121913631
Molecular consequence:
  • NM_000257.4:c.2722C>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
21

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000208505GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)		Pathogenic
(Feb 17, 2022) 		germlineclinical testing

Citation Link,

SCV000280334Stanford Center for Inherited Cardiovascular Disease, Stanford University
no assertion criteria provided
Pathogenic
(Oct 3, 2014) 		germlineclinical testing

SCV000331349Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions)		Pathogenic
(Sep 16, 2015) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided18not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown3not providednot providednot providednot providedclinical testing

Details of each submission

From GeneDx, SCV000208505.13

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Reported in multiple unrelated individuals with HCM referred for genetic testing at GeneDx and in the published literature (Epstein et al., 1992; Atiga et al., 2000; Van Driest et al., 2002; Woo et al., 2003; Alpert et al., 2005; Morita et al., 2008; Rodriguez et al., 2011; Pan et al., 2012; Kapplinger et al., 2014; Murphy et al., 2016; Marian et al., 2018; Mattivi et al., 2020; Burstein et al., 2021; Hathaway et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated L908V increases the velocity of actin filament movement in the in vitro motility assays performed using cardiac or skeletal muscle tissue from L908V heterozygous individuals (Palmiter et al., 2000; Alpert et al., 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9172070, 20560001, 26914223, 8514894, 21642240, 11227787, 10615387, 7731997, 12881443, 23074333, 12473556, 15858117, 18480046, 21310275, 12428185, 9475582, 12975413, 15358028, 24510615, 12820698, 8435239, 1638703, 8483915, 15528230, 28166811, 27532257, 25351510, 27247418, 28606303, 18403758, 29300372, 10725281, 31324451, 31447099, 29540445, 33673806, 32746448, 31006259, 34135346, 32894683, 31996208, 8281650, 31905684, 22555271, 21135372)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided18not providednot providedclinical testingnot provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. GBased on the strong case data, segregation data, and absence in large population samples, we consider it very likely disease causing. Per ClinVar, both LMM (SCV000059471) and Emory (SCV000110306) consider it pathogenic. This variant has been reported in at least 18 unrelated cases of HCM (including the cases in our center). There is very strong segregation data in 3 families and good functional data available. We have seen this variant in two unrelated patients with HCM in our center. Epstein et al. (1992) reported this variant in a very large kindred with very strong segregation data: Leu908Val was present in all 19 affected members of the family, who spanned 3 generations [Fananapazir et al. (1993) appears to discuss this same family.] Van Driest et al. (2002) identified it in 3 unrelated HCM patients at the Mayo Clinic. The same group later reported 8 HCM patients with this variant from their cohort; presumably 3 of these cases are redundant (Bost et al 2014). Van Driest et al. (2004) reported it in 4 unrelated patients, but it’s unclear if these include the 3 from 2002. al-Mahdawi et al. (1993) identified it in one HCM family. Mohiddin et al. (2003) found it in two unrelated HCM cases. Woo et al. (2003) found it in 3 separate families. In one family it segregated with disease in 8 family members from 3 generations (some of them 4th degree relatives). Alpert et al. (2005) found Leu908Val in a family that also carried an Asp906Gly variant in trans—the result of two brothers in one HCM family marrying two sisters in another HCM family. Among family members with only the Leu908Val variant, it segregated with disease in 21 family members. Two individuals with both mutations developed severe HCM. Yu et al. (2005) found it in an Australian family. Morita et al. (2008 + supplemental data) found it in three unrelated HCM cases. Variation at nearby codons of MYH7 (within 10 amino acids to either side) has been associated with disease, supporting the functional importance of this region of the protein. These HCM variants include Ala901Gly, Glu903Lys (Van Driest et al. 2004), Cys905Phe and Asp906Gly (Harvard Sarcomere Protein Gene Mutation Database). I could find no other variants at the same codon (ClinVar, Bos et al 2014 (Mayo cohort of >1000 cases, dbSNP; as of 8 Oct 2014). Mutationtaster predicts it to be disease causing and PolyPhen2 predicts it to be possibly damaging. There is functional data available: Cuda et al. (1993, 1997) took skeletal muscle biopsies from HCM patients with this variant, and showed that the mutant cardiac myosin is also present in skeletal muscle and has abnormal function in an in vitro assay in which actin filaments are translocated by myosin bound to a coverslip surface. Fananapazir et al. (1993) analyzed skeletal muscle biopsies from HCM patients, and found 10 of 13 patients with the L908V mutation to have a myopathy resembling central core disease: a non-progressive skeletal myopathy characterized by loss of mitochondria. Palmiter et al. (2000) found the variant to alter the kinetics of the myosin cross-bridge cycle. Alpert et al. (2005) found Leu908Val to increase the velocity of actin translocation by myosin (isolated from HCM patient muscle biopsies) in vitro. This is a conservative amino acid change from a nonpolar Leucine to a nonpolar Valine. The Leucine at codon 908 is completely conserved across 44 vertebrate species examined. Surrounding residues are also highly conserved. This variant is in the rod domain of the beta-myosin heavy chain protein (Rayment et al. 1995) localized to the coiled-coil alpha-helical S-2 region (Cuda et al. 1997). In total the Leu908Val variant has not been seen in ~7341 published controls and publicly available population datasets. No variation at codon 908 is present in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6500 Caucasian African American individuals (as of 1/15/2012). It was not observed in 841 published controls: Epstein et al. (1992) did not observe the variant in 50 controls. Van Driest et al. (2002) did not report controls. al-Mahdawi et al. (1993) did not find it in 5 controls. Mohiddin et al. (2003) did not find it in 200 controls. Woo et al. (2003) did not find it in 106 controls. Van Driest et al. (2004) did not observe the variant in 100 Caucasian and 100 African American controls (likely redundant with Bos et al 2014). Yu et al. (2005) did not find it in 100 Australian controls matched for ethnicity. Morita et al. (2008) did not find it in 180 ethnicity-matched controls. The Leu908Val variant is present in dbSNP as rs121913631 (“probable-pathogenic”). It was submitted by the OMIM staff at Johns Hopkins.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided18not providednot providednot provided

From Eurofins Ntd Llc (ga), SCV000331349.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not providednot providednot provided

Last Updated: Nov 3, 2024