rs369437262

Positions:

• chr14-23415228-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

This summary comes from the ClinGen Evidence Repository: The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID:30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3 LINK:https://erepo.genome.network/evrepo/ui/classification/CA015944/MONDO:0005045/002

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: MYH7 NM_000257.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:20
• Conservation: PhyloP100: 7.75

Genes affected

MYH7 (HGNC:7577): (myosin heavy chain 7) Muscle myosin is a hexameric protein containing 2 heavy chain subunits, 2 alkali light chain subunits, and 2 regulatory light chain subunits. This gene encodes the beta (or slow) heavy chain subunit of cardiac myosin. It is expressed predominantly in normal human ventricle. It is also expressed in skeletal muscle tissues rich in slow-twitch type I muscle fibers. Changes in the relative abundance of this protein and the alpha (or fast) heavy subunit of cardiac myosin correlate with the contractile velocity of cardiac muscle. Its expression is also altered during thyroid hormone depletion and hemodynamic overloading. Mutations in this gene are associated with familial hypertrophic cardiomyopathy, myosin storage myopathy, dilated cardiomyopathy, and Laing distal myopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH7	NM_000257.4	c.5326A>G	p.Ser1776Gly	missense_variant	37/40	ENST00000355349.4	NP_000248.2
MYH7	NM_001407004.1	c.5326A>G	p.Ser1776Gly	missense_variant	36/39		NP_001393933.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH7	ENST00000355349.4	c.5326A>G	p.Ser1776Gly	missense_variant	37/40	1	NM_000257.4	ENSP00000347507	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251494 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135922

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461894 Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16 AN XY: 727248

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.000646

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74364

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:20

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 16918501, 29300372, 21239446, 11861410, 25961035, 27247418, 23074333, 27532257, 24510615, 29121657, 28518168, 30297972, 31493341, 32420109, 30847666, 37652022, 34542152, 34136434, 34137518, 11861413) -
Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	May 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -

not specified Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 01, 2023	Variant summary: MYH7 c.5326A>G (p.Ser1776Gly) results in a non-conservative amino acid change located in the Myosin tail domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5326A>G has been reported in the literature in individuals affected with HCM (Blair_2002, Fokstuen_2011, Homburger_2017, Walsh_2017, Viswanathan_2017, Kelly_2018, Daoud_2019, vanLint_2019, AlShafai_2021) including reports of co-occurrences of this variant with other pathogenic variants. One study showed limited evidence indicating this variant may segregate with disease (Blair_2002). However, these reports do not provide unequivocal conclusions about association of the variant with HCM. One in vitro study showed that this variant does not affect cMyBP-C attachment to the thick filament, showing no damaing effect of this variant in this context (Flashman_2007). The following publications have been ascertained in the context of this evaluation (PMID: 34137518, 11861413, 30731207, 16918501, 21239446, 27247418, 34136434, 29300372, 31199839, 29121657, 27532257, 30847666). Fourteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with all laboratories classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 29, 2018	The p.Ser1776Gly variant in MYH7 has been identified in at least 12 individuals with HCM (Blair 2002, Fokstuen 2010, Homburger 2016, Walsh 2017, Kelly 2018, Ho 2018, LMM data) and segregated with disease in 1 affected family member (Blair 2 002). It has also been identified in 0.03% (6/19954) of East Asian and 0.02% (5/ 24968) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Comp utational prediction tools and conservation analysis suggest that this variant m ay impact the protein, though this information is not predictive enough to deter mine pathogenicity. Moreover, this variant was classified as a variant of uncert ain significance on December 15, 2016 by the ClinGen-approved Inherited Cardiomy opathy expert panel (SCV000564457.2). In summary, the clinical significance of t he p.Ser1776Gly variant is uncertain due to conflicting evidence. ACMG/AMP Crite ria applied: PP3. -
Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jan 06, 2015	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. p.Ser1776Gly (AGC>GGC): c.5326 A>G in exon 37 of the MYH7 gene (NM_000257.2) We first reviewed this variant in 2011. We re-reviewed them October 15th, 2014 and then again February 20th, 2015. Given the high frequency of Filipino cases and lack of ancestry matched controls we consider this a variant of uncertain significance. The variant has been seen in two published cases of HCM and at least 15 unpublished cases (not including the patient). Ancestry is only available for 11 cases (including this patient); 5 are Asian, 6 are Filipino of those are Asian, as is this patient. At least 4 of 16 total cases (including ours) have another sarcomere variant. This variant has been reported previously in two unrelated cases of HCM (Blair et al 2002, Fokstuen et al 2010). In the family reported by Blair et al (2002) the variant was present in two affected siblings and absent in an unaffected sibling (ancestry not reported). The proband underwent analysis of MYH7, MYBPC3, TNNT2, ACTC2, MYL2 and had no variants in those genes. Cases were recruited in the UK and South Africa.Fokstuen et al (2010) observed the variant in 1 of 122 unrelated HCM patients recruited in Switzerland. They did not provide segregation data. Subjects underwent sequencing of MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC1, TNNC1, PRKAG2, however the authors do not report if any cases had multiple variants. We have seen the variant in one other patient with HCM in our center who is Fillipino. This is a semi conservative amino acid change with a polar Serine replaced with a nonpolar Glycine at codon 1776 of MYH7 gene. The Serine at position 1776 is conserved across mammals and myosin isoforms. Given that this amino acid change is located in a core position of the myosin rod, where a Glycine is expected to be energetically unfavorable, Blair et al (2002) hypothesized that this variant would disrupt the normal coiled-coil structure of myosin. However, this variant did not interfere with binding to myosin binding protein C (Flasshman et al 2007). Variants in nearby codons have been reported in association with cardiomyopathy: p.Glu1768Lys (van Driest et al 2003), p.Thr1775Ile (Bos et al 2014), p.Ala1777Thr (Richard et al 2003, Bos et al 2014), p.His1778Tyr (Alfares et al 2015), . The variant was reported online in 4 of 60705 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of February 23rd, 2015). Specifically, the variant was observed in 2 of 4327 East Asians and 2 of 5203 Africans, . The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). Blair et al (2002) report they did not observe the variant in 200 presumably healthy control individuals. Fokstuen et al (2010) did not analyze teh variant in controls. -

Cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces serine with glycine at codon 1776 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect cMyBP-C attachment to the thick filament (PMID: 16918501). This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy (PMID: 11861413) and in four unrelated individuals with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29121657, 31493341, 33495597). This variant has been identified in 13/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This missense variant replaces serine with glycine at codon 1776 of the MYH7 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant does not affect cMyBP-C attachment to the thick filament (PMID: 16918501). This variant has been reported in two related individuals affected with hypertrophic cardiomyopathy (PMID: 11861413) and in four unrelated individuals with hypertrophic cardiomyopathy (PMID: 27247418, 27532257, 29121657, 31493341, 33495597). This variant has been identified in 13/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Feb 10, 2023	- -

Hypertrophic cardiomyopathy Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1776 of the MYH7 protein (p.Ser1776Gly). This variant is present in population databases (rs369437262, gnomAD 0.03%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 11861413, 27247418, 27532257, 28518168, 29121657). ClinVar contains an entry for this variant (Variation ID: 177629). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect MYH7 function (PMID: 16918501). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	research	Genetics and Genomics Program, Sidra Medicine	-	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen Cardiomyopathy Variant Curation Expert Panel	Dec 15, 2016	The c.5326A>G (p.Ser1776Gly) variant in MYH7 has been reported in 12 individuals with hypertrophic cardiomyopathy (PMID:27532257; PMID:11861413; PMID:21239446; Partners LMM ClinVar SCV000203861.4; SHaRe consortium, PMID: 30297972) but has also been identified in 0.02% (2/8654) of East Asian chromosomes by ExAC (http://exac.broadinstitute.org). Since the MYH7 specifications state that PS4 is only applicable if the variant is absent or rare in large population studies, PS4 criterion was not applied (PMID:29300372). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PP3 -

Hypertrophic cardiomyopathy 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 16, 2021	The inherited c.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene substitutes a very well conserved Serine for Glycine at amino acid 1776/1936 (exon 37/40). This variant is found with low frequency in gnomAD(v3.1.1)(8 heterozygotes, 0 homozygotes; allele frequency: 5.256e-5) suggesting that it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.001) and Pathogenic (REVEL; score:0.776) to the function of the canonical transcript. This variant has been reviewed by ClinGen's Cardiomyopathy Variant Curation Expert Panel classified as a Variant of Uncertain Significance in ClinVar (VarID:177629). The c.5326A>G (p.Ser1776Gly) variant has been reported in multiple individuals with hypertrophic cardiomyopathy [PMID:11861413, 21239446, 31199839, others], and segregated with disease in one set of siblings [PMID:11861413]. However, this variant has also been detected in control populations [PMID:24510615], and functional studies suggest it does not alter the ability to bind myosin-binding protein C[PMID:16918501], although additional studies are needed to confirm this finding. Given conflicting evidence regarding its pathogenicity, the inheritedc.5326A>G (p.Ser1776Gly) variant identified in the MYH7 gene is reported as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genomics Laboratory, Stanford Medicine	Jun 22, 2021	The p.Ser1776Gly variant in the MYH7 gene has been previously reported in several unrelated individuals with hypertrophic cardiomyopathy (Fokstuen et al., 2011; Viswanathan et al., 2017; Walsh et al., 2017; van Lint et al., 2019) and segregated with disease in two affected individuals from one family (Blair et al., 2002). However, in many cases another potentially causative variant was identified. Additionally, this variant has been reported at a high frequency in affected individuals of Asian/Pacific Islander ancestry, a population that is insufficiently represented in population databases. This variant has been identified in 6/19,954 East Asian chromosomes (13/282,892 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a high enough frequency to rule out pathogenicity. •One in vitrostudy suggested that this variant does not disrupt binding to myosin binding C protein (Flashman et al., 2007). The serine at position 1776 is highly conserved. Computational tools predict that the p.Ser1776Gly variant is deleterious; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance ofthe p.Ser1776Glyvariant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -

Dilated cardiomyopathy 1S Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Stanford Medicine

Jun 11, 2021

The p.Ser1776Gly variant in the MYH7 gene has been previously reported in several unrelated individuals with hypertrophic cardiomyopathy (Fokstuen et al., 2011; Viswanathan et al., 2017; Walsh et al., 2017; van Lint et al., 2019) and segregated with disease in two affected individuals from one family (Blair et al., 2002). However, in many cases another potentially causative variant was identified. Additionally, this variant has been reported at a high frequency in affected individuals of Asian/Pacific Islander ancestry, a population that is insufficiently represented in population databases. This variant has been identified in 6/19,954 East Asian chromosomes (13/282,892 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a high enough frequency to rule out pathogenicity. One in vitro study suggested that this variant does not disrupt binding to myosin binding C protein (Flashman et al., 2007) The serine at position 1776 is highly conserved. Computational tools predict that the p.Ser1776Gly variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Ser1776Gly variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PP3] -

Congenital myopathy with fiber type disproportion;C1834481:Dilated cardiomyopathy 1S;C1842160:Myosin storage myopathy;C1850709:Myopathy, myosin storage, autosomal recessive;C3495498:Hypertrophic cardiomyopathy 1;C4552004:MYH7-related skeletal myopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 07, 2021

- -

Primary familial hypertrophic cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

May 18, 2016

- -

MYH7-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

The MYH7 c.5326A>G variant is predicted to result in the amino acid substitution p.Ser1776Gly. This variant has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Blair et al. 2002. PubMed ID: 11861413; Table S4, Kelly et al. 2018. PubMed ID: 29300372; Table S1B, Walsh et al. 2016. PubMed ID: 27532257). It has been reported to segregate with HCM in a family (Blair et al. 2002. PubMed ID: 11861413). This variant has also been found in control individuals in large cohort studies looking at gene burden and penetrance (Dataset S1, Homburger et al. 2016. PubMed ID: 27247418; Table S6, Park et al. 2022. PubMed ID: 34542152). In vitro experimental studies show this variant does not impact cMyBP-C-myosin binding (Flashman et al. 2007. PubMed ID: 16918501); however, protein modeling studies indicate this variant likely affects the coiled-coil structure and filament assembly (Blair et al. 2002. PubMed ID: 11861413). This variant is interpreted as uncertain by the ClinGen Cardiomyopathy Variant Curation Expert Panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/177629/). This variant is reported in 0.030% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2022

The p.S1776G variant (also known as c.5326A>G), located in coding exon 35 of the MYH7 gene, results from an A to G substitution at nucleotide position 5326. The serine at codon 1776 is replaced by glycine, an amino acid with similar properties. This variant has been detected in hypertrophic cardiomyopathy cohorts, although, in some cases, clinical details were limited or it co-occurred with other variants (Fokstuen S et al. J Med Genet. 2011;48(8):572-6; Homburger JR et al. Proc Natl Acad Sci U.S.A. 2016 06;113(24):6701-6; Viswanathan SK et al. PLoS ONE. 2017;12(11):e0187948; Walsh R et al. Genet Med. 2017 02;19(2):192-203). In one study, this variant co-segregated with disease in two affected siblings (Blair E et al. Circ Res. 2002;90(3):263-9). This variant has also been seen in an exome cohort, a control cohort, and a biobank cohort but cardiovascular history was not provided (Pan S et al. Circ Cardiovasc Genet. 2012 5(6):602-10; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7(3):347-61; Park J et al. Hum Mol Genet. 2022 03;31(5):827-837). This variant is located in the LMM protein domain, involved in thick filament assembly supporting contractile function. One in vitro functional study indicated this variant did not disrupt binding to myosin binding protein C, but may affect thick filament structure and stability; however, the physiological relevance of this finding is unclear (Flashman E et al. Biochem J. 2007;401(1):97-102). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
CardioboostCm	Uncertain	0.28
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.044	D
Polyphen		0.80	P
Vest4		0.93
MutPred		0.41		Loss of phosphorylation at S1776 (P = 0.0274);
MVP		0.88
MPC		1.5
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs369437262; hg19: chr14-23884437;